ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.17933A>G (p.His5978Arg)

gnomAD frequency: 0.00002  dbSNP: rs756460900
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000309426 SCV000343852 uncertain significance not provided 2016-07-25 criteria provided, single submitter clinical testing
Invitae RCV000309426 SCV001385198 pathogenic not provided 2021-12-10 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 5978 of the ADGRV1 protein (p.His5978Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome type 2 (PMID: 22147658, 30459346). 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: 289480). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001731567 SCV001983677 pathogenic Usher syndrome 2021-09-14 criteria provided, single submitter clinical testing Variant summary: ADGRV1 c.17933A>G (p.His5978Arg) results in a non-conservative amino acid change located in the GPCR, family 2-like domain (IPR017981) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248956 control chromosomes (gnomAD). c.17933A>G has been reported in the literature in multiple individuals affected with Usher Syndrome (e.g. Besnard_2012, Sloan-Heggen_2016, Fuster-Garcia_2018, Garcia-Garcia_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

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