Submissions for variant NM_032119.4(ADGRV1):c.16331C>A (p.Thr5444Lys)

gnomAD frequency: 0.00039  dbSNP: rs370906851

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180070	SCV000232435	uncertain significance	not provided	2015-02-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765859	SCV000897255	uncertain significance	Usher syndrome type 2C; Febrile seizures, familial, 4	2018-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000180070	SCV001142930	uncertain significance	not provided	2018-12-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000180070	SCV001154447	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180070	SCV001233125	likely benign	not provided	2025-01-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509284	SCV002819880	uncertain significance	not specified	2022-12-28	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.16331C>A (p.Thr5444Lys) 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 0.00034 in 249132 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in ADGRV1 causing Usher Syndrome (0.00034 vs 0.0054), allowing no conclusion about variant significance. c.16331C>A has been reported in the literature in individuals affected with Usher Syndrome/deafness with non-informative genotypes (pathogenicity of the second allele uncertain) (examples: Sloan-Heggen_2016 and Zhou_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816305	SCV005070915	uncertain significance	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000180070	SCV005626524	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Identified phase unknown with a likely benign variant in a patient with hearing loss in published literature (PMID: 26969326); 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: 26969326, 34426522, 37745463, 35813073)
PreventionGenetics, part of Exact Sciences	RCV004553020	SCV004104031	uncertain significance	ADGRV1-related disorder	2023-12-04	no assertion criteria provided	clinical testing	The ADGRV1 c.16331C>A variant is predicted to result in the amino acid substitution p.Thr5444Lys. This variant was reported in the heterozygous state along with a second potentially causative variant (p.Ile508Leu) in an individual with hearing loss (Table S3, Sloan-Heggen. 2016. PubMed ID: 26969326). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.