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Genomic Inform™ Genetic Test Results SUMMARY

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Genomic Inform™ Genetic Test Results SUMMARY Genomic Inform™ Genetic Test Results Patient Ordering physician Specimen Name: ##### ##### ##### ##### Type: Saliva DOB: Jan 01, 1963 Collected: ### ##, #### Test: ######### Report date: ### ##, #### Received: ### ##, #### Test performed: Singleton WGS SUMMARY RISK STATUS: The following are pathogenic/likely pathogenic variants identified in this individual that have been reported to increase the risk to develop the associated diseases: ABCA4 A heterozygous, likely pathogenic variant was identified in the ABCA4 gene. ABCA4-related disease: Heterozygous, pathogenic variants in the ABCA4 gene have been reported to cause Age-related macular degeneration. It should be noted that this is a susceptibility gene and may not confer disease and the visual disturbance may precede ophthalmoscopic findings. Individuals with a heterozygous pathogenic variant in this gene are also at a reproductive risk for the conditions listed under the carrier risk section of this report. UNCERTAIN RISK STATUS: A heterozygous variant of uncertain significance was identified in a gene where the clinical symptoms associated with the disease may overlap with this individual's symptoms of elevated cholesterol levels. Variants of uncertain significance are neither pathogenic nor benign, but are likely to be reclassified over time as more evidence becomes available. Therefore, it is recommended that results containing uncertain variants be reinterpreted periodically to determine if they may be related to disease. LDLR A heterozygous variant of uncertain significance was identified in the LDLR gene. LDLR-related disease Heterozygous (and rarely homozygous) pathogenic variants in the LDLR gene have been reported to cause an inherited form of high cholesterol called familial hypercholesterolemia. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and coronary arteries, which increases risk for cardiovascular disease. CARRIER STATUS: Carriers are typically unaffected themselves but have a risk of passing the variant to their offspring. The reproductive risk for a particular gene or disease is based on whether both parents are carriers for pathogenic changes in the same gene. The following variants indicate this individual is a carrier for the following genes and related diseases: ABCA4 In addition to a personal Age-related macular degeneration risk, this individual is at reproductive risk for the following diseases: Cone-rod dystrophy, a condition associated with a loss of visual sharpness (acuity), an increased sensitivity to light (photophobia), and impaired color vision; Stargardt macular degeneration, characterized by vision loss that worsens over time, particularly affecting central and night vision; and Retinitis pigmentosa. Variantyx Inc 1671 Worcester Rd, Suite 300 +1 617-209-2090 Lab Director: Christine M Stanley, PhD, FACMG ABMGG #2005163 Framingham, MA 01701 [email protected] CLIA #22D2140582, MA License #5438 Page 1/8 Genomic Inform™ Genetic Test Results Patient: ##### ##### DOB: Jan 01, 1963 Test: ######### LAMB2 A likely pathogenic variant was identified in the LAMB2 gene. LAMB2-related disease Pathogenic variants in the LAMB2 gene cause Pierson syndrome (PIERSS) an autosomal recessive disorder characterized by nephrotic syndrome with neonatal onset, diffuse mesangial sclerosis and eye abnormalities with microcoria as the leading clinical features [MIM:609049]. SEPN1 A likely pathogenic variant was identified in the SEPN1 gene. SEPN1-related disease Homozygous and compound heterozygous pathogenic variants in the SEPN1 gene have been reported to cause several disorders: Multiminicore disease, Rigid spine muscular dystrophy, Congenital fiber-type disproportion; and desmin-related myopathy with Mallory body-like inclusions. Together, muscle diseases caused by SELENON gene mutations are known as SELENON-related (or SEPN1-related) myopathies. The occurrence of Multiminicore disease (MMD) in two generations in a few families has been reported, suggestive of autosomal dominant inheritance. No other pathogenic or likely pathogenic structural, mitochondrial, short tandem repeat, or small sequence variants were identified that have been associated with the family history or clinical symptoms provided. No variants were identified in the American College of Medical Genetics and Genomics (ACMG) minimum list of 59 genes to be reported as incidental or secondary findings. There were no pathogenic variants in hereditary cancer genes identified. Follow up recommendations Genetic counseling is recommended to review the personal and reproductive implications of these results. Variants of uncertain significance are neither pathogenic nor benign, but are likely to be reclassified over time as more evidence becomes available. Therefore, it is recommended that results containing uncertain variants be reinterpreted periodically to determine if they may be related to disease. Treatments and agents to avoid for SEPN1-related disease have been reported in Gene Reviews (PMID: 20301467). Variantyx Inc 1671 Worcester Rd, Suite 300 +1 617-209-2090 Lab Director: Christine M Stanley, PhD, FACMG ABMGG #2005163 Framingham, MA 01701 [email protected] CLIA #22D2140582, MA License #5438 Page 2/8 Genomic Inform™ Genetic Test Results Patient: ##### ##### DOB: Jan 01, 1963 Test: ######### Variants in genes linked to increased disease risk Location Variant Disease / Inheritance Pathogenicity ABCA4 c.5882G>A Age-related macular degeneration Likely pathogenic NM_000350.2 p.Gly1961Glu MOI: Autosomal dominant Evidence: PP3, PS1, Heterozygous PP5 rs1800553 LDLR c.2541G>A Familial hypercholesterolaemia Uncertain significance NM_000527.4 p.Pro847Pro MOI: Autosomal dominant Evidence: PP3 Heterozygous rs137853964 ABCA4 NM_000350.2 c.5882G>A p.Gly1961Glu This variant is a Nonsynonymous SNV mutation in the ABCA4 gene. According to published ACMG guidelines the pathogenicity of this variant is classified as Likely Pathogenic based on the following evidence: PP3, PS1, PP5. Zygosity state is Heterozygous. It is a variant with a 0.0113 maximal allele frequency in the population databases available for review. In peer reviewed clinical literature this variant has been reported to be associated with phenotype(s) listed in the Disease/Inheritance field in the table above. Calculated severity score is 0.79 on a scale of 0.0 – 1.0. The gene is considered non-essential and its tolerance score (RVIS) is in the top 86.31%. Additional comments and references: The variant, c.5882G>A identified in the ABCA4 gene in this patient satisfies the following lines of evidence: multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3), same amino acid change as a previously established pathogenic variant regardless of nucleotide change (PS1), reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation (PP5). Based on the ACMG guidelines, the evidence is considered sufficient for classification of this variant as likely pathogenic. 1. Allikmets et al. (1997) Science 277:1805 2. Alapati et al. (2014) Molecular Diagnostic Testing by eyeGENE: Analysis of Patients With Hereditary Retinal Dystrophy Phenotypes Involving Central Vision Loss. IOVS 55:5510 3. Birtel et al. (2018) Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. SCI REP 8:4824 4. Lee et al. (2017) Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent. EJHG 25:735 5. Thiadens et al. (2012) Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. OPHTHALMOL 119:819 LDLR NM_000527.4 c.2479G>A p.Pro847Pro This variant is a Nonsynonymous SNV mutation in the LDLR gene. According to published ACMG guidelines the pathogenicity of this variant is classified as Uncertain Significance based on the following evidence: PP3. Zygosity state is Heterozygous. It is a variant with a 0.0032 maximal allele frequency in the population databases available for review. In peer reviewed clinical literature this variant has been reported to be associated with phenotype(s) listed in the Disease/Inheritance field in the table above. Calculated severity score is 0.92 on a scale of 0.0 – 1.0. The gene is considered non-essential and its tolerance score (RVIS) is in the top 2.03%. Additional comments and references: The variant c.2479G>A, p.Val827Ile identified in the LDLR gene in this patient satisfies the following lines of evidence: multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3). Based on the ACMG guidelines, the evidence Variantyx Inc 1671 Worcester Rd, Suite 300 +1 617-209-2090 Lab Director: Christine M Stanley, PhD, FACMG ABMGG #2005163 Framingham, MA 01701 [email protected] CLIA #22D2140582, MA License #5438 Page 3/8 Genomic Inform™ Genetic Test Results Patient: ##### ##### DOB: Jan 01, 1963 Test: ######### is considered insufficient for classification as either benign or pathogenic and is, therefore, considered a variant of uncertain significance. 1. Hobbs et al. (1992) Hum Mutat 1:445 2. Bertolini et al. (2013) Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. ATHEROS 227:342 3. Dorschner et al. (2013) Actionable, Pathogenic Incidental Findings in 1,000 Participants Exomes AJHG 93:631 4. Durst et
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