ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.3503G>A (p.Arg1168Gln) (rs797044516)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004779 SCV001164262 pathogenic Usher syndrome 2019-09-16 reviewed by expert panel curation The c.3503G>A (p.Arg1168Gln) variant in MYO7A has been detected in at least 4 probands with Usher syndrome. For two of those probands, a pathogenic or suspected-pathogenic variants was observed in trans, and in one individual, the variant was observed with a pathogenic or suspected-pathogenic variant, but it was unclear if phasing was performed (PM3_Strong, PP4; PMID:25404053, 27460420, 28944237). The allele frequency of this variant is 0.004%% (1/26850) of South Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The c.3503G>A (p.Arg1168Gln) variant is located in the last base of the exon, which is part of the 5' consensus sequence, and computational tools suggest an impact to splicing. Furthermore, tThe REVEL computational prediction analysis tool produced a score of 0.9, which is above the threshold necessary to apply PP3. A different likely pathogenic or suspected-pathogenic variant at the same nucleotide (c.3503G>C, Arg1168Pro) has been previously identified in an individual with Usher syndrome who was compound heterozygous for a second pathogenic truncating variant (PMID: 16470552). In addition, a minigene assay demonstrated that the 3503G>C variant led to skipping of exon 27 (PMID: 20052763) suggesting that variants that alter the c.3503G nucleotide may cause abnormal splicing (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Strong, PP4, PM2, PP3, PM5_Supporting.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156269 SCV000205986 uncertain significance not specified 2014-01-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The 3503G>A (Ar g1168Gln) variant in MYO7A has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the f requency of this variant. This variant is located in the last base of exon 27 in the major transcript (NM_000260.3) of MYO7A, which is part of the conserved 5? splice region of intron 27. Computational tools suggest an impact to splicing; h owever, this information is not predictive enough to determine pathogenicity. Ho wever, a different variant at the same nucleotide (3503G>C, Arg1168Pro) has been previously described in an individual with Usher syndrome who was compound hete rozygous for a second pathogenic variant (Jaijo 2006). Functional studies demons trated that the 3503G>C variant led to skipping of exon 27 (Le Guedard-Mereuze 2 010), suggesting that variants that alter the c.3503G nucleotide cause abnormal splicing. In summary, the clinical significance of this variant cannot be determ ined with certainty; however based upon its location within the splice consensus sequence and its predicted impact on splicing, we would lean towards a more lik ely pathogenic role.
Ambry Genetics RCV000623408 SCV000741576 pathogenic Inborn genetic diseases 2016-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000675162 SCV000800779 likely pathogenic Deafness, autosomal recessive 2; Usher syndrome type 1 2017-08-03 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091732 SCV001247935 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Invitae RCV001091732 SCV001398407 pathogenic not provided 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1168 of the MYO7A protein (p.Arg1168Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 27 of the MYO7A coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal recessive Usher syndrome (PMID: 25404053, 27460420, 28944237). ClinVar contains an entry for this variant (Variation ID: 179479). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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