ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.2308G>A (p.Ala770Thr) (rs375253473)

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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,Partners HealthCare Personalized Medicine RCV000220021 SCV000272149 uncertain significance not specified 2017-06-24 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala770Thr var iant in MYO7A has been reported in 1 Asian individual with adult-onset hearing l oss (Ji 2014), and has been identified by our laboratory in 1 Asian individual w ith features of Usher syndrome who carried pathogenic variants in another gene t hat were sufficient to explain their disease (ClinVar Variation ID 229002). It h as also been identified in 0.1% (10/18616) of East Asian chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs37525 3473); however its frequency is not high enough to rule out a pathogenic role. C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, while the clinical si gnificance of the p.Ala770Thr variant is uncertain, these data suggests that it is more likely to be benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756410 SCV000884214 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing The p.Ala770Thr variant (rs375253473) has not been reported in the medical literature; however a similar nearby variant (p.Ala771Ser) has been reported in two patients with Usher type I syndrome, one of whom carried a second PCDH15 variant (Nakanishi 2010 and Yoshimura 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the East Asian population (identified on 10 out of 18,616 chromosomes), and has been reported to the ClinVar database with an uncertain classification (Variation ID: 229002). The alanine at position 770 is moderately conserved considering 13 species and computational analyses of the effects of the p.Ala770Thr variant on protein structure and function provide conflicting results (SIFT: damaging, MutationTaster: polymorphism, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ala770Thr variant with certainty.

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