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

dbSNP: rs111033256

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036506	SCV000060161	pathogenic	Rare genetic deafness	2022-06-30	criteria provided, single submitter	clinical testing	The p.Val239Asp variant in SLC26A4 has been reported in >20 homozygous or compound heterozygous individuals with hearing loss or Pendred syndrome and segregated with disease in at least 10 affected individuals from multiple families (Tekin 2003 PMID: 12974744, Park 2003 PMID: 12676893, Walsh 2005 PMID: 16460646, Anwar 2009 PMID: 19287372, Soh 2015 PMID: 25394566). It has also been identified in 0.14% (7/4828) of South Asian chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org), however this variant is thought to be a founder mutation in this population (Anwar 2009 PMID: 19287372). This variant has also been reported in ClinVar (Variation ID 43566). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function and have shown that protein trafficking is affected and iodide trasport activity is reduced (Walsh 2005 PMID: 16460646, Dossena 2011 PMID: 22116360, Wassano 2020 PMID: 19287372). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred Syndrome. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Moderate, PP3.
Counsyl	RCV000169244	SCV000220521	likely pathogenic	Pendred syndrome	2014-07-18	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724118	SCV000331645	pathogenic	not provided	2016-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724118	SCV000947211	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 239 of the SLC26A4 protein (p.Val239Asp). This variant is present in population databases (rs111033256, gnomAD 0.2%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 12974744, 16460646, 23770805, 25394566). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43566). 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: 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	2023-10-12	criteria provided, single submitter	clinical testing	Common variant accounting for approximately 30% of the mutant alleles of SLC26A4; suggested to be a founder variant in the Pakistani population (Anwar et al., 2009); Published functional studies demonstrate that this variant reduces anion transport activity, affects protein localization and overall severely impairs normal protein function (Park et al., 2003; Dossena et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27771369, 23965030, 33879512, 25394566, 16460646, 12676893, 12974744, 23336812, 30077349, 23504402, 31389194, 30303587, 23770805, 31599023, 32417962, 34171171, 33231815, 32747562, 33199029, 22116360, 19287372)
Revvity Omics, Revvity	RCV000724118	SCV002020678	pathogenic	not provided	2023-06-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169244	SCV002026675	pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
3billion	RCV001004629	SCV002058856	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: VCV000043566, PMID:12676893, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 12676893, 23504402, 30303587, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 31599023, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.935, 3CNET: 0.981, 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: 0.000203, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
King Laboratory, University of Washington	RCV001004629	SCV002059883	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-08-01	criteria provided, single submitter	research	SLC26A4 c.716T>A, p.V239D has been shown to decrease SLC26A4 ion transport activity (PMID: 22116360). The variant is homozygous in 10 Palestinian children from a single kindred with pre-lingual hearing loss (Abu Rayyan 2020). It is present in 1 of 1300 Palestinian controls, as a heterozygote, and present in 51/251468 alleles on gnomAD, all heterozygotes.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001814026	SCV002061796	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-12-28	criteria provided, single submitter	clinical testing	PS3, PM3_strong, PP1, PP3, PM1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001004629	SCV002557167	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to aspartic acid (exon 6). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (51 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (sulfate permease family domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; Khan, M. et al. (2013)). (P) 1002 - Moderate functional evidence supporting abnormal protein function (Dossena, S. et al. (2011); Walsh, T. et al. (2006)). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
MGZ Medical Genetics Center	RCV000169244	SCV002580662	pathogenic	Pendred syndrome	2022-01-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001814026	SCV002776735	pathogenic	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome	2021-12-06	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000724118	SCV002818283	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
UAEU Genomics Laboratory, United Arab Emirates University	RCV001004629	SCV003926556	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-11-22	criteria provided, single submitter	research	The missense variant NM_000441.2(SLC26A4):c.716T>A (p.Val239Asp) has been observed in several individuals and families affected with SLC26A4-related conditions (PMID: 12974744, 16460646, 23770805, 25394566). The Val239Asp is a common variant in the SLC26A4 gene that is associated with Pendred syndrome in the Pakistani population (PMID:19287372). This variant is observed in 51/30616 (0.1666%) alleles from individuals of gnomAD South Asian background in the gnomAD dataset (Genome Aggregation Database et al., 2020), but was not seen in the homozygous state. Computational prediction tools and conservational analysis predict that the p.Val239Asp missense change has a damaging effect on the protein structure or function. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000169244	SCV004048529	pathogenic	Pendred syndrome		criteria provided, single submitter	clinical testing	The missense variant c.716T>A (p.Val239Asp) in SLC26A4 gene has been observed in several individuals and families affected with SLC26A4-related conditions (Tekin M et.al.,2003). Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic retuclum, and impaired protein function (Walsh T et.al.,2006). This variant has been reported to the ClinVar database as Pathogenic. The p.Val239Asp variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.02028 % is reported in gnomAD. The amino acid Val at position 239 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val239Asp in SLC26A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004629	SCV004201823	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-27	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001004629	SCV004697373	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	clinical testing	The missense variant c.716T>A (p.Val239Asp) in the SLC26A4 gene has been reported previously in homozygous state in individuals affected with hearing loss. Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic reticulum, and impaired protein function (Walsh et al., 2006; Dossena et al., 2011). This variant is reported with the allele frequency (0.02%) in the gnomAD and novel (not in any individuals) in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/Pathogenic (Multiple submission). The amino acid Valine at position 239 is changed to an Aspartic Acid changing the protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Val239Asp in SLC26A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001004629	SCV005016575	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-03-14	criteria provided, single submitter	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	Autosomal recessive nonsyndromic hearing loss 4	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	Hearing loss, autosomal recessive		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724118	SCV001951462	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724118	SCV001969734	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000169244	SCV001994882	not provided	Pendred syndrome		no assertion provided	literature only