ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.5618G>A (p.Arg1873Gln) (rs397516322)

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Total submissions: 7
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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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000594226 SCV000706352 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing
Invitae RCV000594226 SCV001412414 uncertain significance not provided 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1873 of the MYO7A protein (p.Arg1873Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397516322, ExAC 0.02%). This variant has been observed in individuals affected with nonsyndromic deafness (PMID: 23208854, 27068579). It is also known as p.Arg1835Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 43292). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: 28472130, 16679490). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
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)
Laboratory for Molecular Medicine, Partners HealthCare 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 Deafness, autosomal recessive 2 2018-02-15 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000594226 SCV001958143 likely pathogenic not provided no assertion criteria provided clinical testing

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