ClinVar Miner

Submissions for variant NM_032119.4(ADGRV1):c.13996A>G (p.Ile4666Val) (rs765672841)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523138 SCV000617516 uncertain significance not specified 2017-08-18 criteria provided, single submitter clinical testing The I4666V variant in the ADGRV1 gene has been reported previously in association with early onset hearing loss (Miyagawa et al., 2013). The I4666V variant is observed in 6/26640 (0.02%) alleles in the ExAC dataset (Lek et al., 2016). The I4666V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I4666V as a variant of uncertain significance.
Invitae RCV001049967 SCV001214050 uncertain significance not provided 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 4666 of the ADGRV1 protein (p.Ile4666Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs765672841, ExAC 0.4%). This variant has not been reported in the literature in individuals with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449395). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The valine 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 RCV001155819 SCV001317283 uncertain significance Usher syndrome, type 2C 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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