Submissions for variant NM_153676.4(USH1C):c.216G>A (p.Val72=)

gnomAD frequency: 0.00002  dbSNP: rs151045328

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824776	SCV000064958	pathogenic	Rare genetic deafness	2012-04-30	criteria provided, single submitter	clinical testing	The c.216G>A variant in USH1C has been reported in the homozygous or compound he terozygous state in at least 70 individuals with Usher syndrome (Roux 2011, Bitn er-Glindzicz 2000, DeAngelis 2001, Ebermann 2007, Lentz 2007, Lentz 2005, Lentz 2010, Ouyang 2003, Savas 2002, Zwaenepoel 2001). The variant has been shown to c reate a cryptic splice site and produce a 35-bp deletion in the RNA transcript i n lymphoblasts. This 35-bp deletion leads to a frameshift and premature terminat ion codon 189 bases downstream. In summary, this variant meets criteria to be cl assified as pathogenic for autosomal recessive Usher syndrome.
Eurofins Ntd Llc (ga)	RCV000724016	SCV000229080	pathogenic	not provided	2014-06-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763237	SCV000893870	pathogenic	Usher syndrome type 1C; Autosomal recessive nonsyndromic hearing loss 18A; Usher syndrome type 1	2021-07-29	criteria provided, single submitter	clinical testing
Invitae	RCV000724016	SCV001223706	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change affects codon 72 of the USH1C mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH1C protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs151045328, gnomAD 0.008%). This variant has been observed in individuals with Usher syndrome 1C (PMID: 11810303, 15578223, 15660226, 17407589). It is commonly reported in individuals of Acadian ancestry (PMID: 17407589, 18665195). ClinVar contains an entry for this variant (Variation ID: 5143). Studies have shown that this variant results in introduction of a cryptic splice site and introduces a premature termination codon (PMID: 10973248, 15578223). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000724016	SCV001779205	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	cDNA analysis demonstrated that the c.216 G>A variant creates a new splice site and results in an out-of-frame deletion of 35 nucleotides (Bitner Glindzicz et al., 2000; Lentz et al., 2005); This variant is associated with the following publications: (PMID: 23380860, 12630964, 17407589, 11139240, 21228398, 28041643, 10973248, 15578223, 21436283, 11810303, 29276601, 32581362, 33089500)
Revvity Omics, Revvity	RCV000724016	SCV002020831	pathogenic	not provided	2020-08-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504855	SCV002548390	pathogenic	Usher syndrome	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: USH1C c.216G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splice donor site located two base bairs proximal to this variant. At least one publication reports experimental evidence that this variant affects mRNA splicing due to the creation of a new splice site within exon 3 two base pairs proximal to the site of this variant (Bitner-Glindzicz_2000). The variant allele was found at a frequency of 3.6e-05 in 251060 control chromosomes. c.216G>A has been reported in the literature as a founder mutation of Acadian origin in homozygous and compound heterozygous genotypes among individuals affected with Usher Syndrome (example, Quyang_2003, Bukakowska_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence from a knock in mouse model that demonstrated early onset dual impairment of vision and hearing (Lentz_2010). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005450	SCV002767681	pathogenic	Usher syndrome type 1C	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (exon 3 of 27) (PMID: PMID: 10973248, 15578223, 20613545). (P) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant is known as the Acadian allele which causes the most severe form of Usher syndrome type 1 (ClinVar, Deafness Variation Database, PMID: 29276601). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Baylor Genetics	RCV000984012	SCV004207629	pathogenic	Autosomal recessive nonsyndromic hearing loss 18A	2023-10-22	criteria provided, single submitter	clinical testing
OMIM	RCV000005450	SCV000025632	pathogenic	Usher syndrome type 1C	2002-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000005450	SCV000086931	not provided	Usher syndrome type 1C		no assertion provided	literature only
GeneReviews	RCV000220605	SCV000268750	not provided	Usher syndrome type 1		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504855	SCV000598661	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000984012	SCV000789704	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 18A	2017-02-14	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724016	SCV001959184	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724016	SCV001964647	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000005450	SCV002087709	pathogenic	Usher syndrome type 1C	2020-02-10	no assertion criteria provided	clinical testing