ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2017-06-13 criteria provided, single submitter clinical testing The L326Q variant in the MYO7A gene has been reported previously in the homozygous state in a family with hearing loss (Riazuddin et al., 2008). A single L326Q variant has also been reported in family with retinitis pigmentosa and hearing loss, considered atypical Usher syndrome (Le Quesne Stabej et al., 2012). The L326Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L326Q variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L326Q as a variant of uncertain significance.
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.

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