Submissions for variant NM_000441.2(SLC26A4):c.1692dup (p.Cys565fs)

dbSNP: rs746427774

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000770866	SCV000924202	pathogenic	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	research
Invitae	RCV001232740	SCV001405308	pathogenic	not provided	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys565Metfs*9) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs746427774, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hearing loss (PMID: 18167283, 19287372, 20842945, 22412181). ClinVar contains an entry for this variant (Variation ID: 627475). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001785722	SCV002026957	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001785722	SCV002548017	pathogenic	Pendred syndrome	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.1692dupA (p.Cys565MetfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250614 control chromosomes. c.1692dupA has been reported in the literature in the compound heterozygous state together with other Pendred syndrome-associated SLC26A4 pathogenic variants (including c.1229C>T and c.919-2A>G) in multiple individuals affected with hearing loss (example Sloan-Heggen_2016, Xiang_2019, Liu_2020, Wang_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000770866	SCV004201869	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-09-11	criteria provided, single submitter	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770866	SCV000902376	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV001785722	SCV002080005	pathogenic	Pendred syndrome	2021-02-10	no assertion criteria provided	clinical testing