Submissions for variant NM_032119.4(ADGRV1):c.11974G>A (p.Asp3992Asn)

gnomAD frequency: 0.00131  dbSNP: rs201386977

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155111	SCV000204797	likely benign	not specified	2013-03-14	criteria provided, single submitter	clinical testing	p.Asp3992Asn in exon 58 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.4% (59/15416) of European chrom osomes and in 0.4% (4/944) of Latino chromosomes by the Exome Aggregation Consor tium (http://exac.broadinstitute.org/; dbSNP rs201386977).
GeneDx	RCV000585241	SCV000321754	benign	not provided	2019-04-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25262649, 25404053, 27460420, 22952768, 30245029, 31047384, 32707200)
Eurofins Ntd Llc (ga)	RCV000585241	SCV000345478	uncertain significance	not provided	2016-09-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585241	SCV000693179	likely benign	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000585241	SCV000840638	uncertain significance	not provided	2018-04-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000585241	SCV000884985	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000585241	SCV001038889	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001153109	SCV001314364	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000585241	SCV001552655	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ADGRV1 p.Asp3992Asn variant was identified in 2 of 896 proband chromosomes (frequency: 0.002) from individuals or families with Usher syndrome (Eandi_2017_PMID:29142287; Bonnet_2016_PMID:27460420). The variant was also identified in dbSNP (ID: rs201386977), ClinVar (classified as a VUS by GeneDx, EGL Genetics, Athena Diagnostics, ARUP and Praxis fuer Humangenetik Tuebingen and as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 320 of 228350 chromosomes at a frequency of 0.001401 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 54 of 9380 chromosomes (freq: 0.005757), Latino in 60 of 28672 chromosomes (freq: 0.002093), Other in 11 of 6242 chromosomes (freq: 0.001762), European (non-Finnish) in 168 of 99320 chromosomes (freq: 0.001692), South Asian in 19 of 25506 chromosomes (freq: 0.000745), European (Finnish) in 5 of 22700 chromosomes (freq: 0.00022) and African in 3 of 20596 chromosomes (freq: 0.000146), while the variant was not observed in the East Asian population. The p.Asp3992 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585241	SCV001959086	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000585241	SCV001968567	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000585241	SCV002034409	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551343	SCV004720018	likely benign	ADGRV1-related disorder	2019-06-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).