ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.2476G>A (p.Ala826Thr) (rs368341987)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000787987 SCV000927011 uncertain significance Usher syndrome 2019-02-06 reviewed by expert panel curation The c.2476G>A (p.Ala826Thr) variant in MYO7A has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). It has been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). The filtering allele frequency of the p.Ala826Thr variant in the MYO7A gene is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI) and this variant is not statistically enriched in cohorts of Usher (0.8%; Fisher's exact p value =0.3262) when compared to the South Asian population in gnomAD (0.55%) (PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). Due to the lack of adequately large case-control analyses in the South Asian population, the ClinGen Hearing Loss Expert Panel believes that the evidence for this variant is inconclusive. In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the HL EP-specified ACMG/AMP criteria applied: BA1, PM3, PP1, PP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154342 SCV000204005 uncertain significance not specified 2017-10-03 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Illumina Clinical Services Laboratory,Illumina RCV000406568 SCV000374294 benign Deafness, autosomal dominant 11 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000303529 SCV000374295 pathogenic MYO7A-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The MYO7A c.2476G>A (p.Ala826Thr) missense variant has been reported in six studies in which it is found in a total of 19 patients with Usher syndrome including in 13 in a homozygous state, in five in a compound heterozygous state and in one in a heterozygous state (Adato et al. 1997; Riazuddin et al. 2008; Le Quesne Stabej et al. 2012; Shahzad et al. 2013; Vona et al. 2014; Bonnet et al. 2016). The p.Ala826Thr variant is present in a heterozygous state in two of 1214 control chromosomes and is reported at a frequency of 0.01471 in the Indian Telugu from the UK population of the 1000 Genomes project. The p.Ala826Thr variant is described as being located in the neck of the MYO7A protein within a motif whose sequence matches the consensus sequence of calmodulin-binding IQ motifs and is expected to impair the calmodulin chain-binding function of the protein. Based on the evidence, the p.Ala826Thr is classified as pathogenic for Usher Syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000576432 SCV000678174 likely pathogenic Deafness, autosomal recessive 2; Usher syndrome type 1 2016-12-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000994688 SCV001148375 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001003087 SCV001163348 pathogenic Usher syndrome type 1 criteria provided, single submitter clinical testing
Invitae RCV000994688 SCV001228536 uncertain significance not provided 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 826 of the MYO7A protein (p.Ala826Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. While this variant is present in population databases (rs368341987), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with Usher syndrome as homozygous in multiple consanguineous families (PMID: 9382091, 29490346). ClinVar contains an entry for this variant (Variation ID: 177732). 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.
GenomeConnect, ClinGen RCV000844912 SCV000986719 not provided Deafness, autosomal dominant 11; Deafness, autosomal recessive 2; Usher syndrome type 1 no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 01/15/2018 by GTR ID Blueprint Genetics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003087 SCV001161146 likely pathogenic Usher syndrome type 1 2019-06-23 no assertion criteria provided research

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