Submissions for variant NM_032119.4(ADGRV1):c.6901C>T (p.Gln2301Ter)

gnomAD frequency: 0.00004  dbSNP: rs121909762

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000007200	SCV000459098	likely pathogenic	Usher syndrome type 2C	2016-09-19	criteria provided, single submitter	clinical testing	The ADGRV1 c.6901C>T (p.Gln2301Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The variant was first reported by Weston et al. (2004) in a total of six individuals with Usher syndrome, including four siblings (including a pair of identical twins) who were homozygous for the variant, a sporadic case from a consanguineous family who was homozygous, and a sporadic case who was heterozygous with a second unidentified variant. The p.Gln2301Ter variant was also identified in a heterozygous state in the unaffected father of the siblings. Sujirakul et al. (2015) identified an individual with autosomal recessive retinitis pigmentosa who carried the p.Gln2301Ter variant and a second heterozygous variant, though the phase of the variants is unclear. Schuerch et al. (2016) found the p.Gln2301Ter variant in a homozygous state in an individual with an unspecified phenotype. The p.Gln2301Ter variant was absent from 190 control chromosomes (Weston et al. 2004), but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Gln2301Ter variant is classified as likely pathogenic for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Eurofins Ntd Llc (ga)	RCV000727026	SCV000705015	pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844603	SCV000710853	pathogenic	Rare genetic deafness	2017-12-14	criteria provided, single submitter	clinical testing	The p.Gln2301X variant in ADGRV1 has been reported in the homozygous or compound heterozygous state with another loss-of-function variant in 3 individuals with Usher syndrome and segregated with disease in 2 affected relatives from 1 family (Weston 2004, Sujirakul 2015). This variant has been identified in 14/276946 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs121909762). It has also been reported in ClinVar (Varia tion ID: 6798). Although this variant has been seen in the general population, i ts frequency is low enough to be consistent with a recessive carrier frequency f or Usher syndrome. This nonsense variant leads to a premature termination codon at position 2301, which is predicted to lead to a truncated or absent protein. L oss of function of the ADGRV1 gene is an established disease mechanism in autoso mal recessive Usher syndrome type 2. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon predicted impact to the protein and the identification of the variant in homozygosity or compound heterozygosity in affected individuals. ACMG/AMP Cr iteria applied: PVS1; PM3_Strong.
GeneDx	RCV000727026	SCV000890167	pathogenic	not provided	2022-10-04	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23891399, 25525159, 14740321, 18463160, 26164827, 28041643, 15671307, 32581362, 32037395)
Fulgent Genetics, Fulgent Genetics	RCV000763550	SCV000894367	pathogenic	Usher syndrome type 2C; Febrile seizures, familial, 4	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727026	SCV001578460	pathogenic	not provided	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2301*) 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). This variant is present in population databases (rs121909762, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ADGRV1-related conditions (PMID: 14740321, 26164827). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6798). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000007200	SCV004183501	pathogenic	Usher syndrome type 2C	2023-10-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505021	SCV005726308	pathogenic	Usher syndrome	2024-11-15	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.6901C>T (p.Gln2301X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.8e-05 in 249006 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (4.8e-05 vs 0.0054), allowing no conclusion about variant significance. c.6901C>T has been reported in the literature in multiple individuals affected with Usher Syndrome (example: Weston_2004). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 14740321). ClinVar contains an entry for this variant (Variation ID: 6798). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000007200	SCV000027396	pathogenic	Usher syndrome type 2C	2004-02-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505021	SCV000599111	pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research