ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.596G>T (p.Ser199Ile) (rs61745496)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755794 SCV000883368 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing The p.Ser199Ile variant (rs61745496) has not been reported in the medical literature or gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with an Ashkenazi Jewish population frequency of 0.8 percent (identified on 83 out of 10,142 chromosomes). The serine at position 199 is highly conserved (Alamut v.2.9.0) and computational analyses of the effects of the p.Ser199Ile variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ser199Ile variant with certainty.
Illumina Clinical Services Laboratory,Illumina RCV001154052 SCV001315372 uncertain significance Usher syndrome, type 2C 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000755794 SCV001386367 uncertain significance not provided 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 199 of the ADGRV1 protein (p.Ser199Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs61745496, ExAC 0.2%). This variant has not been reported in the literature in individuals with ADGRV1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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