Submissions for variant NM_000441.2(SLC26A4):c.-4+5G>A

gnomAD frequency: 0.00006  dbSNP: rs727503425

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151882	SCV000200378	likely pathogenic	Rare genetic deafness	2014-06-17	criteria provided, single submitter	clinical testing	The -4+5G>A variant in SLC26A4 has been identified in one individual with hearin g loss and EVA by our laboratory (LMM unpublished data) likely in trans with an other pathogenic variant SLC26A4 variant. In addition, this variant has not bee n identified in large population studies and is located in the 5' splice region. Computational tools suggest a possible impact to splicing; though this informat ion is not predictive enough to determine pathogenicity. In summary, this varia nt is likely pathogenic.
King Laboratory, University of Washington	RCV003230418	SCV003844110	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-02-28	criteria provided, single submitter	research	This variant was found in compound heterozygosity with an SLC26A4 splicing variant that is known to be pathogenic, in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no history of childhood-onset hearing loss. This variant is a single base pair substitution within the 5’ UTR that is predicted to interfere with normal splicing. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 2 heterozygotes on gnomAD. Based on compound heterozygosity with a loss-of-function variant, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226214	SCV003922666	uncertain significance	not specified	2023-03-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737234	SCV005345500	uncertain significance	SLC26A4-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The SLC26A4 c.-4+5G>A variant is located in the 5' untranslated region. This variant is located in the 5' untranslated region and is predicted to possibly impact splicing (Alamut Visual v2.11). To our knowledge, this variant has not been reported in the literature but has been reported in ClinVar as being likely in trans to a second pathogenic variant in a patient with hearing loss and enlarged vestibular aqueduct (https://www.ncbi.nlm.nih.gov/clinvar/variation/165245/). This variant is reported in 0.24% of alleles in individuals of Latino descent, and in 2 of ~31,000 total alleles in the gnomAD database. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.