Submissions for variant NM_000441.2(SLC26A4):c.2174_2177dup (p.Leu727fs)

gnomAD frequency: 0.00005  dbSNP: rs1421964916

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055826	SCV001220236	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu727Tyrfs*28) 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 (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Pendred syndrome, non-syndromic hearing loss, or hearing loss and dilatation of the vestibular aqueduct (PMID: 17125574, 23638949, 24224479, 25394566). This variant is also known as 2177-2178insCTAT. ClinVar contains an entry for this variant (Variation ID: 851431). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473658	SCV004201858	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001275120	SCV004223014	pathogenic	Pendred syndrome	2023-11-21	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.2174_2177dupCTAT (p.Leu727TyrfsX28) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251280 control chromosomes. c.2174_2177dupCTAT has been reported in the literature in individuals affected with Pendred Syndrome (Ladsous_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24224479). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003473658	SCV005399892	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 4, with enlarged vestibular aqueduct (#MIM600791) and Pendred syndrome (#MIM274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMIDs: 20301640, 24599119). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by diagnostic laboratories in ClinVar and has been reported in individuals with hearing loss and enlarged vestibular aqueducts (PMIDs: 17125574, 23638949). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Statistical Genetics, Columbia University	RCV004794482	SCV005415632	pathogenic	Hearing loss, autosomal recessive	2024-11-08	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005036355	SCV005673666	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2024-03-13	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275120	SCV001459942	pathogenic	Pendred syndrome	2020-09-16	no assertion criteria provided	clinical testing