ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.77C>A (p.Ala26Glu)

dbSNP: rs369125667
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154340 SCV000204003 pathogenic Rare genetic deafness 2017-02-21 criteria provided, single submitter clinical testing The p.Ala26Glu variant has been previously reported in been reported in 5 indivi duals with Usher syndrome, 3 of whom also carried a second pathogenic or likely pathogenic MYO7A variant (Bharadwaj 2000, Jaijo 2007, Le Quesne Stabej 2012). T his variant has also been identified in 1/22234 Finnish and 1/110588 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs369125667). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carri er frequency for Usher syndrome. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this va riant meets criteria to be classified as pathogenic for autosomal recessive Ushe r syndrome based on the information described above.
Labcorp Genetics (formerly Invitae), Labcorp RCV002516104 SCV003440568 pathogenic not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 26 of the MYO7A protein (p.Ala26Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive Usher syndrome type 1 (PMID: 10930322, 17361009, 22135276, 27460420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 177731). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. For these reasons, this variant has been classified as Pathogenic.

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