ClinVar Miner

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

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Total submissions: 6
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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.
Counsyl RCV000576432 SCV000678174 likely pathogenic Deafness, autosomal recessive 2; Usher syndrome, type 1 2016-12-06 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000406568 SCV000374294 benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
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.
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

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