ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.3827C>T (p.Ser1276Leu) (rs369458838)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171535 SCV001334320 uncertain significance Usher syndrome 2020-02-19 reviewed by expert panel curation The allele frequency of the p.Ser1276Leu variant in the MYO7A gene is 0.008% (1/12706) of African chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a likely pathogenic variant (PM3; Partners LMM internal data SCV000204707.4). The REVEL computational prediction analysis tool produced a score of 0.77, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PP3, PM2_Supporting, PM3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155024 SCV000204707 likely pathogenic Rare genetic deafness 2013-03-16 criteria provided, single submitter clinical testing The Ser1276Leu variant in MYO7A has not been reported in the literature nor iden tified by our laboratory in any other families. However, identification of this variant in trans with another MYO7A in this individual?s daughter who has clinic al features of Usher syndrome increases the likelihood that this variant is path ogenic. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ser1276Leu varian t may impact the protein. It should be noted that this variant has been identifi ed in 1/3582 (0.02%) African American chromosomes from a broad population (NHLBI Exome Sequencing Project; http://evs.gs.washington.edu/EVS), however, its frequ ency is low enough to be consistent with a recessive carrier frequency. In summa ry, this variant is likely to be pathogenic, though additional studies are requi red to fully establish its clinical significance.
Counsyl RCV000675121 SCV000800675 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2018-03-19 criteria provided, single submitter clinical testing

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