Submissions for variant NM_032119.4(ADGRV1):c.7468G>A (p.Ala2490Thr)

gnomAD frequency: 0.00025  dbSNP: rs143632883

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039629	SCV000063318	uncertain significance	not specified	2015-02-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala2490Thr va riant in GPR98 has been previously reported in 1 individual with hearing loss; h owever a variant affecting the remaining copy of GPR98 was not identified in thi s individual (LMM unpublished data). In addition, this variant has been identifi ed in 30/66628 (0.05%) European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143632883). The alanine (Ala) res idue at position 2490 is not well conserved in some mammals and most evolutionar y distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools do not provide strong supp ort for or against an impact to the protein. In summary, while the clinical sign ificance of the p.Ala2490Thr variant is uncertain, the conservation data and its frequency in the general population suggest that it is more likely to be benign .
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057194	SCV001221674	likely benign	not provided	2025-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001155420	SCV001316846	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001057194	SCV001472268	uncertain significance	not provided	2019-09-25	criteria provided, single submitter	clinical testing	The ADGRV1 c.7468G>A; p.Ala2490Thr variant (rs143632883), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 46373). This variant is found in the general population with an overall allele frequency of 0.02% (67/280370 alleles) in the Genome Aggregation Database. The alanine at codon 2490 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Ala2490Thr variant is uncertain at this time.
Baylor Genetics	RCV001330110	SCV001521714	uncertain significance	Febrile seizures, familial, 4	2020-01-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002483008	SCV002776371	uncertain significance	Usher syndrome type 2C; Febrile seizures, familial, 4	2022-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513553	SCV003688945	uncertain significance	Inborn genetic diseases	2022-12-19	criteria provided, single submitter	clinical testing	The c.7468G>A (p.A2490T) alteration is located in exon 33 (coding exon 33) of the ADGRV1 gene. This alteration results from a G to A substitution at nucleotide position 7468, causing the alanine (A) at amino acid position 2490 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.