rs111033256
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000441.2(SLC26A4):c.716T>A(p.Val239Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000954 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151978Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251468Hom.: 0 AF XY: 0.000302 AC XY: 41AN XY: 135912
GnomAD4 exome AF: 0.000101 AC: 147AN: 1461808Hom.: 0 Cov.: 31 AF XY: 0.000147 AC XY: 107AN XY: 727210
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152096Hom.: 0 Cov.: 30 AF XY: 0.0000807 AC XY: 6AN XY: 74346
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:10Other:1
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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. -
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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. -
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Severe to Profound SNHL -
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Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:7Other:1
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The observed missense variant c.716T>Ap.Val239Asp in SLC26A4 gene has been reported previously in individuals with SLC26A4-related conditions. Experimental studies have shown that this missense change affects SLC26A4 function Soh LM, et al., 2015; Shahzad M, et al., 2013; Dossena S, et al., 2011. This variant is reported with the allele frequency 0.02% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. 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. Multiple lines of computational evidence Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
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. -
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. -
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. -
in vitro experiment -
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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 -
not provided Pathogenic:6
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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) -
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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. -
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Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
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PS3, PM3_strong, PP1, PP3, PM1 -
Hearing loss, autosomal recessive Pathogenic:1
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Rare genetic deafness Pathogenic:1
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. -
Deafness Pathogenic:1
PM3_VeryStrong, PS3, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at