ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.977T>A (p.Leu326Gln) (rs797044491)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001252672 SCV001428431 likely pathogenic Usher syndrome 2020-06-23 reviewed by expert panel curation The c.977T>A (p.Leu326Gln) variant in MYO7A was absent from gnomAD v2.1.1 (PM2).This variant has been detected in at least 2 probands with Usher syndrome. For 1 of those patients, a pathogenic or suspected-pathogenic variants was observed in trans, and in 1 the variant was observed in the homozygous state (PM3; SCV000199549.4, PMID:18181211; ClinVar ID: 164663). At least one of these probands was confirmed to have both hearing loss and retinitis pigmentosa, features highly specific for Usher syndrome (PP4). The REVEL computational prediction tool produced a score of 0.991, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP3, PP4).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151482 SCV000199549 likely pathogenic Rare genetic deafness 2013-05-07 criteria provided, single submitter clinical testing The Leu326Gln variant in MYO7A has been reported in two individuals with clinica l features of Usher syndrome, one of whom was homozygous ( Riazuddin 2008, Le Qu esne Stabej 2012). In addition, this variant was identified in trans with a seco nd pathogenic MYO7A variant in this individual, supporting a likely pathogenic r ole. Furthermore, computational analyses (biochemical amino acid properties, con servation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact t he protein. In summary, this variant is likely to be pathogenic, though addition al studies are required to fully establish its clinical significance.
GeneDx RCV000498129 SCV000589578 uncertain significance not provided 2020-03-03 criteria provided, single submitter clinical testing Observed with no second variant in an individual with hearing loss in published literature (Le Quesne Stabej et al., 2012); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18181211, 22135276)
Counsyl RCV000675063 SCV000800529 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2017-05-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778340 SCV000914540 uncertain significance MYO7A-Related Disorders 2017-09-13 criteria provided, single submitter clinical testing The MYO7A c.977T>A (p.Leu326Gln) missense variant has been reported in two studies in which it is found in two individuals with MYO7A-Related Disorders. The p.Leu326Gln variant was found in a homozygous state in one individual with Usher syndrome and in a heterozygous state (with a presumed unknown second allele) in one individual with atypical Usher syndrome (Riazuddin et al. 2008; Le Quesne Stabej et al. 2012). The p.Leu326Gln variant was absent from 1164 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database and is in a region of good sequence coverage, so the variant is presumed to be rare. Another variant with a different amino acid change at the same residue (p.Leu326Pro) has also been detected in an individual with type 1 Usher syndrome in a compound heterozygous state (Sodi et al. 2014). This variant has not been reported in association with autosomal dominant or autosomal recessive nonsyndromic hearing loss. Based on the evidence, the p.Leu326Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000498129 SCV001495637 uncertain significance not provided 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 326 of the MYO7A protein (p.Leu326Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Usher syndrome (PMID: 18181211, 25558175). ClinVar contains an entry for this variant (Variation ID: 164664). 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: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
University of Washington Center for Mendelian Genomics, University of Washington RCV001291467 SCV001479971 likely pathogenic Deafness, autosomal recessive no assertion criteria provided research

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