Submissions for variant NM_032119.4(ADGRV1):c.15608A>G (p.Glu5203Gly)

gnomAD frequency: 0.00038  dbSNP: rs202106463

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039536	SCV000063225	benign	not specified	2015-06-02	criteria provided, single submitter	clinical testing	Glu5203Gly in exon 74 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (85/11574) of Latino chromosom es, including 3 homozygotes, by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs202106463).
Eurofins Ntd Llc (ga)	RCV000724510	SCV000232420	uncertain significance	not provided	2014-12-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000724510	SCV000969533	likely benign	not provided	2020-10-26	criteria provided, single submitter	clinical testing
Invitae	RCV000724510	SCV001024546	benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001155929	SCV001317396	uncertain significance	Usher syndrome type 2C	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000724510	SCV002544962	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	ADGRV1: BP1, BP4, BS1
Ambry Genetics	RCV002513548	SCV003758817	uncertain significance	Inborn genetic diseases	2021-10-18	criteria provided, single submitter	clinical testing	The c.15608A>G (p.E5203G) alteration is located in exon 74 (coding exon 74) of the ADGRV1 gene. This alteration results from a A to G substitution at nucleotide position 15608, causing the glutamic acid (E) at amino acid position 5203 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724510	SCV001549504	likely benign	not provided		no assertion criteria provided	clinical testing	The ADGRV1 p.Glu5203Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs202106463) and in ClinVar (classified as a VUS by EGL Genetic Diagnostics and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 265 of 280608 chromosomes (1 homozygous) at a frequency of 0.000944 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: Other in 32 of 7142 chromosomes (freq: 0.004481), Ashkenazi Jewish in 45 of 10352 chromosomes (freq: 0.004347), Latino in 140 of 35374 chromosomes (freq: 0.003958), European (non-Finnish) in 41 of 128386 chromosomes (freq: 0.000319), South Asian in 6 of 30602 chromosomes (freq: 0.000196) and African in 1 of 24192 chromosomes (freq: 0.000041); it was not observed in the East Asian or European (Finnish) populations. The p.Glu5203Gly residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.