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

dbSNP: rs797044491

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252672	SCV001428431	likely pathogenic	Usher syndrome	2024-09-24	reviewed by expert panel	curation	The c.977T>A variant in MYO7A is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 326 (p.Leu326Gln). The highest population filtering allele frequency in gnomAD v4.1 is 0.00002995 (7/91056 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.991, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 3 individuals with autosomal recessive Usher syndrome. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (1.5 PM3 points, SCV000199549.4, SCV000589578.6, Laboratory for Molecular Medicine, GeneDx). One individual was homozygous for the variant (0.5 PM3 points, PMID: 18181211) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000199549.4, Laboratory for Molecular Medicine). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024)
Laboratory for Molecular Medicine, Mass General Brigham 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	likely pathogenic	not provided	2024-08-22	criteria provided, single submitter	clinical testing	Observed with no second variant in an individual with hearing loss in published literature (PMID: 22135276); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33269433, 33671976, 18181211, 22135276, LimSO2021[Article])
Illumina Laboratory Services, Illumina	RCV004528877	SCV000914540	uncertain significance	MYO7A-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498129	SCV001495637	likely pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu326 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 25558175), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 164664). This missense change has been observed in individual(s) with Usher syndrome (PMID: 18181211). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 326 of the MYO7A protein (p.Leu326Gln).
Myriad Genetics, Inc.	RCV001810427	SCV002060245	uncertain significance	Usher syndrome type 1	2021-11-10	criteria provided, single submitter	clinical testing	NM_000260.3(MYO7A):c.977T>A(L326Q) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. L326Q has been observed in cases with relevant disease (PMID: 22135276, 18181211, 33269433, 30303587). Functional assessments of this variant are not available in the literature. L326Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.977T>A(L326Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Neuberg Centre For Genomic Medicine, NCGM	RCV004576924	SCV005060956	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2		criteria provided, single submitter	clinical testing	The observed missense c.977T>A(p.Leu326Gln) variant in MYO7A gene has been reported previously in homozygous and compound heterozygous state in multiple individuals affected with MYO7A-related disorders (Sodi A, et al., 2014; Le Quesne Stabej P, et al., 2012; Riazuddin S, et al., 2008). The p.Leu326Gln variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid change p.Leu326Gln in MYO7A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 326 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005008058	SCV005632200	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2024-01-08	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291467	SCV001479971	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research