Submissions for variant NM_000441.2(SLC26A4):c.918+2T>C

gnomAD frequency: 0.00001  dbSNP: rs912147281

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000409090	SCV001163091	pathogenic	Pendred syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV001217246	SCV001389080	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the SLC26A4 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 SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 23918157, 27214836). ClinVar contains an entry for this variant (Variation ID: 370108). 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.
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	RCV000770872	SCV001809841	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	research
Genome-Nilou Lab	RCV000770872	SCV002027029	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000409090	SCV002027040	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409090	SCV002060182	pathogenic	Pendred syndrome	2021-10-27	criteria provided, single submitter	clinical testing	NM_000441.1(SLC26A4):c.918+2T>C is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.918+2T>C has been observed in cases with relevant disease (PMID: 23918157, 23336812, 27214836). Functional assessments of this variant are not available in the literature. c.918+2T>C has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_000441.1(SLC26A4):c.918+2T>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409090	SCV003928983	pathogenic	Pendred syndrome	2023-04-05	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.918+2T>C 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. Two computational tools predict a significant impact on normal splicing, suggesting the variant abolishes a canonical 5' splicing donor site, while one predicts the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251256 control chromosomes. c.918+2T>C has been reported in the literature in individuals affected with hearing loss (Chai_2013, Goncalves_2016, Rentorff_2013, Cengiz_2017), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000770872	SCV004201888	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001217246	SCV005080313	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29739340, 31589614, 27214836, 23918157, 28964290, 26990548, 36147510, 24007330, 23336812, 31541171)
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770872	SCV000902385	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000409090	SCV002079982	pathogenic	Pendred syndrome	2020-05-26	no assertion criteria provided	clinical testing