ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.2527G>A (p.Val843Met) (rs140559111)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171529 SCV001334314 uncertain significance Usher syndrome 2020-03-19 reviewed by expert panel curation The filtering allele frequency (the lower threshold of the 95% CI of 23/22568) of the p.Val843Met variant in the MYO7A gene is 0.07% for South Asian chromosomes by gnomAD v2.1.1, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Of note, this variant was reported in 5 individuals with hearing loss, though without any evidence of pathogenicity (PM3 not met; SCV000779779.2, SCV000059741.6, SCV000702277.2). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036089 SCV000059741 uncertain significance not specified 2017-10-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val843Met var iant in MYO7A has been previously identified by our laboratory in one Caucasian individual with hearing loss. It has also been identified in 0.1% (23/22644) of South Asian chromosomes and in 72/163744 of the total chromosomes with the highe st frequency of 0.1% (23/22644) in South Asian chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140559111). Com putational prediction tools and conservation analysis suggest that the p.Val843M et variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val843Met variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015 ).
Illumina Clinical Services Laboratory,Illumina RCV000367440 SCV000374302 uncertain significance Deafness, autosomal recessive 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000274914 SCV000374303 likely benign Deafness, autosomal dominant 11 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000318308 SCV000374304 uncertain significance Usher syndrome type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000658008 SCV000702277 uncertain significance not provided 2016-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000658008 SCV000779779 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The V843M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 23/22644 (0.1016%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). V843M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000658008 SCV001418150 uncertain significance not provided 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 843 of the MYO7A protein (p.Val843Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. While this variant is present in population databases (rs140559111), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 43185). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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