ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.716T>A (p.Val239Asp) (rs111033256)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169244 SCV000220521 likely pathogenic Pendred syndrome 2014-07-18 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724118 SCV000331645 pathogenic not provided 2016-07-15 criteria provided, single submitter clinical testing
Invitae RCV000724118 SCV000947211 pathogenic not provided 2020-10-11 criteria provided, single submitter clinical testing This sequence change replaces valine with aspartic acid at codon 239 of the SLC26A4 protein (p.Val239Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is present in population databases (rs111033256, ExAC 0.2%). This variant has been observed in several individuals and families affected with SLC26A4-related conditions (PMID: 12974744, 16460646, 23770805, 25394566). ClinVar contains an entry for this variant (Variation ID: 43566). Experimental studies have shown that this missense change has a deleterious effect on protein function and localization (PMID: 16460646, 22116360). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169244 SCV001337950 pathogenic Pendred syndrome 2020-01-14 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.716T>A (p.Val239Asp) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain 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 0.0002 in 251468 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred syndrome (0.0002 vs 0.0035). c.716T>A has been reported in the literature in numerous individuals affected with Pendred syndrome (eg. Khan_2013, Dossena_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic retuclum, and impaired protein function (Walsh_2006, Dossena_2011). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000724118 SCV001766345 pathogenic not provided 2021-05-05 criteria provided, single submitter clinical testing V239D is a common variant accounting for approximately 30% of the mutant alleles of SLC26A4; it has been suggested V239D may be a founder variant in the Pakistani population (Anwar et al., 2009); Published functional studies demonstrated that this variant severely impairs normal protein function (Park et al., 2003; Dossena et al., 2011); This variant is associated with the following publications: (PMID: 32417962, 31599023, 23770805, 30303587, 31389194, 23336812, 23504402, 23965030, 30077349, 12974744, 12676893, 16460646, 25394566, 22116360, 27771369, 19287372)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036506 SCV000060161 pathogenic Rare genetic deafness 2008-09-19 no assertion criteria provided clinical testing
Hereditary Research Laboratory, Bethlehem University RCV000169244 SCV000538118 pathogenic Pendred syndrome 2016-06-04 no assertion criteria provided research Severe to Profound SNHL
National Institute of Sensory Organs,National Hospital Organization Tokyo Medical Center RCV001004629 SCV000994874 affects Deafness, autosomal recessive 4, with enlarged vestibular aqueduct 2019-08-20 no assertion criteria provided literature only in vitro experiment
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000169244 SCV001133020 likely pathogenic Pendred syndrome 2019-09-26 no assertion criteria provided clinical testing
Natera, Inc. RCV000169244 SCV001455802 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV001291246 SCV001479671 likely pathogenic Deafness, autosomal recessive no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000724118 SCV001951462 likely pathogenic not provided no assertion criteria provided clinical testing

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