Submissions for variant NM_000441.2(SLC26A4):c.269C>T (p.Ser90Leu)

dbSNP: rs370588279

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169192	SCV000220439	likely pathogenic	Pendred syndrome	2014-06-20	criteria provided, single submitter	literature only
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000785622	SCV000924203	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	research
3billion	RCV000785622	SCV002058680	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188842, PMID:12676893, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.892, 3CNET: 0.971, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850391	SCV002278324	pathogenic	not provided	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 90 of the SLC26A4 protein (p.Ser90Leu). This variant is present in population databases (rs370588279, gnomAD 0.01%). This missense change has been observed in individuals with pre-lingual deafness or nonsyndromic enlargement of vestibular aqueduct (PMID: 12676893, 17443271, 20842945, 25372295, 27247933, 27792752, 32681043; Invitae). ClinVar contains an entry for this variant (Variation ID: 188842). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 32417962). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000785622	SCV004201852	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2023-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169192	SCV005185150	pathogenic	Pendred syndrome	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.269C>T (p.Ser90Leu) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251466 control chromosomes. c.269C>T has been reported in the literature in the presumed compound heterozygous and homozygous states in multiple individuals affected with autosomal recessive nonsyndromic deafness and/or Pendred Syndrome (example, Gao_2016, Dahl_2013, Sloan-Heggen_2016, Zhang_2019, Chandru_2020, Anwar_2009) and has been suggested to be a founder mutation (example, Anwar_2009). These data indicate that the variant is very likely to be associated with disease. Functional analysis in vitro found this variant results in severely decreased transport activity and cellular mislocalization (example, Wasano_2020). The following publications have been ascertained in the context of this evaluation (PMID: 19287372, 32417962, 23555729, 27792752, 26969326, 31599023, 31107121). ClinVar contains an entry for this variant (Variation ID: 188842). Based on the evidence outlined above, the variant was classified as pathogenic.
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	RCV000785622	SCV000994861	affects	Autosomal recessive nonsyndromic hearing loss 4	2019-08-20	no assertion criteria provided	clinical testing	in vitro experiment