Submissions for variant NM_153676.4(USH1C):c.496+1G>T

dbSNP: rs138138689

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666962	SCV000791340	pathogenic	Usher syndrome type 1C; Autosomal recessive nonsyndromic hearing loss 18A	2017-05-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090231	SCV001245636	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001090231	SCV001400823	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the USH1C 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 USH1C are known to be pathogenic (PMID: 10973247, 17407589, 20301442, 21203349). This variant is present in population databases (rs138138689, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Usher syndrome (PMID: 17407589, 25468891). ClinVar contains an entry for this variant (Variation ID: 551814). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001090231	SCV001447683	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001090231	SCV002020830	pathogenic	not provided	2019-07-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001090231	SCV002540365	pathogenic	not provided	2022-06-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 25468891, 24498627, 25525159, 17407589, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV002499156	SCV002814821	pathogenic	Usher syndrome type 1C; Autosomal recessive nonsyndromic hearing loss 18A; Usher syndrome type 1	2021-07-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465458	SCV004207640	pathogenic	Autosomal recessive nonsyndromic hearing loss 18A	2024-02-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829837	SCV002077657	pathogenic	Usher syndrome type 1C	2020-07-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004756004	SCV005357977	pathogenic	USH1C-related disorder	2024-08-08	no assertion criteria provided	clinical testing	The USH1C c.496+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the compound heterozygous and in the presumed compound heterozygous state in individuals with Usher syndrome 1 (Ebermann et al. 2007. PubMed ID: 17407589; supplementary data, Bujakowska et al. 2014. PubMed ID: 25468891). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/551814/). Variants that disrupt the consensus splice donor site in USH1C are expected to be pathogenic. This variant is interpreted as pathogenic.