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

gnomAD frequency: 0.00002  dbSNP: rs369458838

Total submissions: 5

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	2023-01-24	reviewed by expert panel	curation	The NM_000260.4:c.3827C>T variant in the MYO7A gene is a missense variant predicted to cause substitution of serine to leucine at amino acid 1276 (p.Ser1276Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0078% (1/12706) in African/African American population ( PM2_Supporting, BS1, and BA1 are not met). 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 computational predictor REVEL gives a score of 0.769, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM3, PP3. (VCEP specifications version 2.0.0; Dec 21, 2022)
Laboratory for Molecular Medicine, Mass General Brigham 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	Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2018-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850120	SCV002168732	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1276 of the MYO7A protein (p.Ser1276Leu). This variant is present in population databases (rs369458838, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 178283). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. 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.
Breakthrough Genomics, Breakthrough Genomics	RCV001850120	SCV005190485	uncertain significance	not provided		criteria provided, single submitter	not provided