ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.5648G>A (p.Arg1883Gln) (rs111033215)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672100 SCV000797165 likely pathogenic Deafness, autosomal recessive 2; Usher syndrome, type 1 2018-01-16 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000036199 SCV000891609 likely pathogenic Usher syndrome, type 1 2017-12-30 criteria provided, single submitter curation
GeneDx RCV000413954 SCV000490900 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing The R1883Q missense variant in the MYO7A gene has been reported previously in association with Usher syndrome type IB, and has been reported in trans with a pathogenic variant on the opposite allele (in trans) in multiple individuals (Ouyang et al., 2005; Nakanishi et al., 2010; Bonnet et al., 2011; Le Quesne Stabej et al., 2012). The R1883Q variant is observed in 3/34194 (0.009%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The R1883Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We classify this variant as pathogenic.
Invitae RCV000413954 SCV000964064 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1883 of the MYO7A protein (p.Arg1883Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs111033215, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with Usher syndrome (PMID: 22135276, 20844544, 21873662, 21569298). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 43294). 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"). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844722 SCV000059851 pathogenic Rare genetic deafness 2018-06-26 criteria provided, single submitter clinical testing The p.Arg1883Gln variant in MYO7A has been reported in 4 individuals with Usher Syndrome Type I (USH1), all of whom also carried a second pathogenic variant (Ou yang 2005, Nakanishi 2010, Bonnet 2011, Le Quesne Stabej 2012, Jacobson 2011). T he p.Arg1883Gln variant has been identified in 0.0088% (3/34194) Latino chromoso mes and 0.004% (10/274046) of total chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033215). Although this variant has been seen in the general population, its overall frequency is low en ough to be consistent with a recessive carrier frequency. Computational predicti on tools and conservation analysis suggest that the p.Arg1883Gln variant may imp act the protein. In summary, this variant meets criteria to be classified as pat hogenic for autosomal recessive Usher syndrome based upon multiple occurrences a s a compound heterozygous variant with pathogenic variants in the same gene in i ndividuals with Usher syndrome, low frequency in the gnomAD database, and predic ted impact on protein. ACMG/AMP criteria applied: PM3_Very Strong, PM2_Supportin g, PP3, PP4.

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