Submissions for variant NM_000260.4(MYO7A):c.1258A>T (p.Lys420Ter)

gnomAD frequency: 0.00002  dbSNP: rs782539587

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000601432	SCV000710850	pathogenic	Rare genetic deafness	2017-07-11	criteria provided, single submitter	clinical testing	The p.Lys420X variant in MYO7A has been identified in the homozygous or compound heterozygous state in 6 individuals with clinical features of Usher syndrome (B onnet 2016, Le Quesne Stabej 2012, Shahzad 2013). In one study, this variant was identified in the homozygous state in 4 separate families of Pakistani descent with histories of consanguinity and segregated in over 10 affected family member s (Shahzad 2013). It has also been identified in 4/235612 chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7825 39587); however, this frequency is low enough to be consistent with a carrier fr equency for recessive Usher syndrome. The p.Lys420X nonsense variant leads to a premature termination codon at position 420, which is predicted to lead to a tru ncated or absent protein. Loss of MYO7A gene function is an established disease mechanism for autosomal recessive Usher syndrome. In summary, this variant meet s criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, homozygosity and compound zygosit y in affected individuals, segregation evidence, and low frequency in the genera l population.
CeGaT Center for Human Genetics Tuebingen	RCV001091730	SCV001247931	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001091730	SCV002157629	pathogenic	not provided	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys420*) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is present in population databases (rs782539587, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with MYO7A-related conditions (PMID: 23770805, 29692870, 31479088). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 504508). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV003447544	SCV004175320	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2023-02-09	criteria provided, single submitter	clinical testing	The MYO7A c.1258A>T variant is classified as a PATHOGENIC variant (PVS1, PM3_Strong) This variant is a single nucleotide change in exon 12/49 of the MYO7A gene, which is predicted to result in premature termination of the protein product at codon 420, causing loss of normal protein function (PVS1). The variant has been reported homozygous or compound heterozygous with another pathogenic MYO7A variant in multiple unrelated individuals affected with hearing loss or Usher syndrome (PMID: 22135276, 23770805, 27460420, 29692870, 31479088) (PM3_Strong). The variant has been reported in dbSNP (rs782539587) but is rare in population databases (gmomAD v2: 4/124267, 0 homozygotes). The variant has been reported in ClinVar (Variation ID: #504508) and HGMD (Accession no.: CM071018) as pathogenic/disease causing.
GeneDx	RCV001091730	SCV005079314	pathogenic	not provided	2024-03-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 16963483, 29692870, 31479088, 31456290, 31541171, 31964843)
Fulgent Genetics, Fulgent Genetics	RCV003447544	SCV005632210	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2024-04-15	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770845	SCV000902346	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2019-02-26	no assertion criteria provided	case-control
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003083	SCV001161142	pathogenic	Usher syndrome type 1	2019-06-23	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291469	SCV001479973	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research