Submissions for variant NM_032119.4(ADGRV1):c.14973-2A>G

gnomAD frequency: 0.00009  dbSNP: rs371981035

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039531	SCV000063220	pathogenic	Rare genetic deafness	2020-07-03	criteria provided, single submitter	clinical testing	The c.14973-2A>G variant in ADGRV1 has been reported in 1 individual with Usher syndrome who harbored a second variant in ADGRV1 and segregated with disease in 1 affected relative (LMM internal data). It has also been identified in 0.16% (12/7704) of Ashkenazi Jewish chromosomes and 1/84474 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 46275). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the ADGRV1 gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM3, PP1, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041197	SCV001204799	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 73 of the ADGRV1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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 (rs371981035, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with Usher syndrome (PMID: 31456290, 31980526, 32037395; internal data). ClinVar contains an entry for this variant (Variation ID: 46275). 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.
Blueprint Genetics	RCV001073981	SCV001239547	likely pathogenic	Retinal dystrophy	2018-09-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155052	SCV003844329	likely pathogenic	Usher syndrome	2023-02-28	criteria provided, single submitter	clinical testing	Variant summary: ADGRV1 c.14973-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site and four predict the variant creates/strengthens a cryptic 3' acceptor site downstream. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.3e-05 in 158958 control chromosomes, found exclusively within the Ashkenazi Jewish subpopulation of the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ADGRV1 causing Usher Syndrome (6.3e-05 vs 0.0054), allowing no conclusion about variant significance. c.14973-2A>G has been reported in the literature in individuals affected with Usher Syndrome (e.g. Zampaglione_2020, Sharon_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001041197	SCV005080430	likely pathogenic	not provided	2024-06-21	criteria provided, single submitter	clinical testing	Reported in association with inherited retinal diseases in published literature but with limited clinical and segregation information (PMID: 32037395, 31456290); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31456290, 31964843, 32037395, 31980526)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786311	SCV005398971	pathogenic	Usher syndrome type 2C	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2C (MIM#605472). (I) 0106 - This gene is associated with autosomal recessive disease. The association between monoallelic variants and febrile seizures, familial, 4 (MIM#604352) has not been established (PanelApp Australia). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 13 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3: 1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic/likely pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in the literature as homozygous in an individual with Usher syndrome (PMID: 37798099). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005031476	SCV005672733	likely pathogenic	Usher syndrome type 2C; Febrile seizures, familial, 4	2024-02-08	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002859	SCV001160886	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research