rs527236133

Positions:

• chr5-90692659-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000405460.9(ADGRV1):​c.7006C>T​(p.Arg2336Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2336R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ADGRV1 ENST00000405460.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.45

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-90692659-C-T is Pathogenic according to our data. Variant chr5-90692659-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 143160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90692659-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.7006C>T	p.Arg2336Ter	stop_gained	32/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.7006C>T	p.Arg2336Ter	stop_gained	32/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244570 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458918 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 2C Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.R2336* in ADGRV1 (NM_032119.4) has been previously reported in 1 Chinese individual with Usher syndrome (Jiang et al, 2015). This variant is predicted to cause loss of normal protein function through protein truncation. The p.R2336* variant is a loss of function variant in the gene ADGRV1, which is intolerant of Loss of Function variants. The amino acid change p.Arg2336Ter in ADGRV1 is predicted as conserved by GERP++ across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This sequence change creates a premature translational stop signal (p.Arg2336*) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658, 26226137, 30718709, 31047384, 32467589). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 143160). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 26338283). -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 23, 2016

The p.Arg2336X variant in GPR98 has been previously reported in 1 Chinese indivi dual with Usher syndrome who was compound heterozygous for a second truncating v ariant in GPR98 (Jiang 2015). This variant has not been identified in large pop ulation studies. This nonsense variant leads to a premature termination codon at position 2336, which is predicted to lead to a truncated or absent protein. Los s of GPR98 function is an established disease mechanism in autosomal recessive U sher syndrome. In summary, this variant meets criteria to be classified as patho genic for autosomal recessive Usher syndrome based upon the predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.26
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs527236133; hg19: chr5-89988476; COSMIC: COSV67995225; COSMIC: COSV67995225;