Submissions for variant NM_000260.4(MYO7A):c.5618G>A (p.Arg1873Gln)

gnomAD frequency: 0.00006  dbSNP: rs397516322

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089676	SCV001245159	pathogenic	Usher syndrome	2019-11-26	reviewed by expert panel	curation	The allele frequency of the p.Arg1873Gln variant in the MYO7A gene is 0.008% (2/24854) of European 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 2 probands with hearing loss and 2 probands with Usher syndrome. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, for 1 proband a pathogenic or suspected-pathogenic was suspected in trans, and for 1 of the probands, a rare variant of uncertain significance was observed in trans (PM3_Strong; PMID:23208854, 28000701, 29196752, Partners LMM internal data SCV000059849.6). The variant has been reported to segregate with hearing loss in one affected family member (PP1, Partners LMM internal data SCV000059849.6). A different pathogenic missense variant (p.Arg1873Trp) has been previously identified at this codon of MYO7A which may indicate that this residue is critical to the function of the protein (PM5; p.Arg1873Trp ClinVar Variation ID 43291). The REVEL computational prediction analysis tool produced a score of 0.936, which is above the threshold necessary to apply PP3. At least one of the above patients with the variant in this gene displayed features of Usher syndrome (PP4; Partners LMM internal data SCV000059849.6). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PM5, PP1, PP3, PP4.
Eurofins Ntd Llc (ga)	RCV000594226	SCV000706352	uncertain significance	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Invitae	RCV000594226	SCV001412414	likely pathogenic	not provided	2023-12-28	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 1873 of the MYO7A protein (p.Arg1873Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 23208854, 27068579). This variant is also known as p.Arg1835Gln. ClinVar contains an entry for this variant (Variation ID: 43292). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. This variant disrupts the p.Arg1873 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16679490, 28472130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV000594226	SCV001766145	uncertain significance	not provided	2019-09-09	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: 27068579, 16963483, 23208854)
Fulgent Genetics, Fulgent Genetics	RCV002504884	SCV002814765	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 11; Autosomal recessive nonsyndromic hearing loss 2; Usher syndrome type 1	2021-07-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036197	SCV000059849	likely pathogenic	Rare genetic deafness	2011-03-25	no assertion criteria provided	clinical testing	The Arg1873Gln variant in MYO7A has been identified in one proband with Usher ty pe I (Cremers 2007). In addition, this residue is highly conserved across evolut ionary distant species and computational analyses (PolyPhen2, SIFT) suggest that the variant may impact the protein. Furthermore, a different variant at the sam e position, Arg1873Trp, has been reported in five probands with Usher syndrome T ype 1 and is classified as pathogenic. In summary, the Arg1873Gln variant is lik ely pathogenic.
Counsyl	RCV000672711	SCV000797845	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 2	2018-02-15	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000594226	SCV001958143	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000594226	SCV001971748	likely pathogenic	not provided		no assertion criteria provided	clinical testing