Submissions for variant NM_000441.2(SLC26A4):c.1264-1G>C

dbSNP: rs111033311

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036433	SCV000060088	pathogenic	Rare genetic deafness	2008-08-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000169533	SCV000221012	likely pathogenic	Pendred syndrome	2015-01-08	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378587	SCV001576189	likely pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 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 (rs111033311, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Pendred syndrome (PMID: 14679580, 15689455, 19204907). ClinVar contains an entry for this variant (Variation ID: 43500). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000169533	SCV002026923	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482976	SCV002786573	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2022-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169533	SCV003922667	likely pathogenic	Pendred syndrome	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1264-1G>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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250736 control chromosomes (gnomAD). c.1264-1G>C has been reported in the literature in individuals affected with Pendred Syndrome (example: Pryor_2004, Prasad_2004, and Rodrigues-Paris_2010). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003473264	SCV004201905	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-07-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001378587	SCV004702777	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SLC26A4: PVS1, PM2
Natera, Inc.	RCV000169533	SCV001459924	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing