Submissions for variant NM_032119.4(ADGRV1):c.3974C>T (p.Thr1325Met)

gnomAD frequency: 0.00007  dbSNP: rs756414393

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000659018	SCV000780821	uncertain significance	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764616	SCV000895723	uncertain significance	Usher syndrome type 2C; Febrile seizures, familial, 4	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000659018	SCV001202716	likely benign	not provided	2024-08-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001155124	SCV001316533	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375131	SCV001572092	likely pathogenic	Abnormal activity of mitochondrial respiratory chain	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Moderate, PP3_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282295	SCV002570965	uncertain significance	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.3974C>T (p.Thr1325Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248924 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (4.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3974C>T has been reported in the literature as a non-informative genotype (second allele/genotype not specified) in at-least one individual affected with features of Usher Syndrome (example, Krawitz_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25333064). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004547830	SCV004113906	uncertain significance	ADGRV1-related disorder	2023-01-19	criteria provided, single submitter	clinical testing	The ADGRV1 c.3974C>T variant is predicted to result in the amino acid substitution p.Thr1325Met. This variant was reported in an individual with Usher syndrome (Krawitz et al 2014. PubMed ID: 25333064). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-89949365-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV000659018	SCV005628305	uncertain significance	not provided	2024-07-16	criteria provided, single submitter	clinical testing	Reported without a second variant in a patient with Usher syndrome in published literature (PMID: 25333064); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25333064, 31964843)