Submissions for variant NM_000260.4(MYO7A):c.3719G>A (p.Arg1240Gln)

gnomAD frequency: 0.00005  dbSNP: rs111033178

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000504703	SCV000059774	pathogenic	Usher syndrome	2019-07-31	criteria provided, single submitter	clinical testing	The Arg1240Gln variant in MYO7A has been reported in at least 14 probands with Usher syndrome (Jacobson 2008, Bharadwaj 2000, Gerber 2006, Jaijo 2007, Jaijo 2009, Janecke 1999, Pennings 2006, Pennings 2004, Roux 2006). Eleven of these probands were homozygous or compound heterozygous. It has also segregated in at least one affected sibling as observed by testing in our laboratory, and it has been reported in ClinVar (Variation ID 43218). This variant has been identified in 0.01% (12/80298) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PP1_Supporting, PP4.
GeneDx	RCV000256123	SCV000321919	pathogenic	not provided	2020-06-19	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18463160, 16679490, 20513143, 21436283, 19683999, 25468891, 16652077, 16400615, 17361009, 27068579, 28559085, 10094549, 10930322, 15043528, 21569298, 16963483, 26969326, 22135276, 15221449, 9354784, 28041643, 31479088, 31980526, 32581362, 31589614, 32467589, 33576794, 33576163, 10612833)
CeGaT Center for Human Genetics Tuebingen	RCV000256123	SCV000608608	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	MYO7A: PM3:Very Strong, PM2, PM5, PP1, PP3
Ambry Genetics	RCV000623302	SCV000741118	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763279	SCV000893923	pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2022-04-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004528176	SCV000914542	pathogenic	MYO7A-related disorder	2018-10-05	criteria provided, single submitter	clinical testing	The MYO7A c.3719G>A (p.Arg1240Gln) missense variant has been reported in at least 11 studies in which it is found in 26 individuals with Usher syndrome type 1 including five homozygotes, 18 compound heterozygotes, two heterozygotes, and in one individual in a double heterozygous state with a variant in the USH2A gene (Janecke et al. 1999; Bharadwaj et al. 2000; Pennings et al. 2004; Gerber et al. 2006; Pennings et al. 2006; Roux et al. 2006; Jaijo et al. 2007; Jacobsen et al. 2008; Jaijo et al. 2010; Bonnet et al. 2011; Le Quesne Stabej et al. 2012). While this variant has not been reported in conjunction with nonsyndromic hearing loss, disease risk cannot be ruled out. The variant was not found in at least 1075 healthy controls (Janecke et al. 1999; Roux et al. 2006; Jaijo et al. 2010; Bonnet et al. 2011) and is reported at a frequency of 0.000723 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the combined evidence, the p.Arg1240Gln variant is classified as pathogenic 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	RCV000256123	SCV000955876	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1240 of the MYO7A protein (p.Arg1240Gln). This variant is present in population databases (rs111033178, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10930322, 15043528, 16652077, 17361009, 18463160, 20513143, 21569298, 21873662, 22135276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43218). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg1240 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been observed in individuals with MYO7A-related conditions (PMID: 24199935), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075882	SCV001241523	pathogenic	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000036122	SCV005013287	pathogenic	Usher syndrome type 1	2024-04-24	criteria provided, single submitter	clinical testing
GeneReviews	RCV000036122	SCV000268744	not provided	Usher syndrome type 1		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504703	SCV000599121	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000984006	SCV000788911	pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2017-01-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001272514	SCV001454586	pathogenic	Usher syndrome type 1B	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000256123	SCV001923520	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000256123	SCV001954855	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256123	SCV001975636	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528176	SCV004119534	pathogenic	MYO7A-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The MYO7A c.3719G>A variant is predicted to result in the amino acid substitution p.Arg1240Gln. This variant has been reported to be causative for autosomal recessive Usher syndrome (Roux et al. 2006. PubMed ID: 16679490; Bharadwaj et al. 2000. PubMed ID: 10930322; Bonnet et al. 2011. PubMed ID: 21569298; supplementary data, Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.