ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.4666G>A (p.Glu1556Lys) (rs200955930)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724689 SCV000227850 uncertain significance not provided 2015-04-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000176233 SCV000711043 uncertain significance not specified 2017-06-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Glu1556Lys va riant in GPR98 has not been previously reported in the literature, but has been reported in ClinVar (Variation ID:195624). This variant has been identified in 0 .09% (110/120782) of European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org; dbSNP rs200955930). Although this varian t has been seen in the general population, its frequency is not high enough to r ule out a pathogenic role. Computational prediction tools and conservation analy ses suggest that this variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. The glutamic acid (Glu) at position 1556 is not highly conserved in mammals and evolutionary distant speci es, and 2 mammals (mouse and opossum) carry a lysine (Lys), raising the possibil ity that this change at this position may be tolerated. In summary, while the cl inical significance of the p.Glu1556Lys variant is uncertain, these data suggest that it is more likely to be benign.
Invitae RCV000724689 SCV001210142 uncertain significance not provided 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1556 of the ADGRV1 protein (p.Glu1556Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs200955930, ExAC 0.2%). This variant has not been reported in the literature in individuals with ADGRV1-related disease. ClinVar contains an entry for this variant (Variation ID: 195624). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV001151342 SCV001312463 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.

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