chr7-107674970-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.626G>T(p.Gly209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,932 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: 0.000362 AC: 55AN: 152052Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000302 AC: 76AN: 251470Hom.: 0 AF XY: 0.000272 AC XY: 37AN XY: 135910
GnomAD4 exome AF: 0.000760 AC: 1111AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.000727 AC XY: 529AN XY: 727244
GnomAD4 genome AF: 0.000362 AC: 55AN: 152052Hom.: 0 Cov.: 30 AF XY: 0.000283 AC XY: 21AN XY: 74288
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:6
NM_000441.1(SLC26A4):c.626G>T(G209V) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: 11932316, 24224479, 15689455, 19509082, 17503324, 9618166, 16570074, 16283880, 18285825 and 10190331. Classification of NM_000441.1(SLC26A4):c.626G>T(G209V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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PS3, PM3_Strong, PP3 -
Variant summary: SLC26A4 c.626G>T (p.Gly209Val) 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 0.0003 in 251470 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0003 vs 0.0035), allowing no conclusion about variant significance. c.626G>T has been reported in the literature in both homozygous and compound heterozygous individuals affected with Pendred Syndrome and non-syndromic deafness (e.g., Campbell_2001, Hutchin_2005). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11317356, 16283880). Multiple submitters have reported 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 pathogenic. -
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:6
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The SLC26A4 c.626G>T (p.G209V) variant has been previously reported in multiple individuals with Pendred syndrome or DFNB4 nonsyndromic hearing loss. This variant is predicted to change an amino acid that is well-conserved across species (PMID: 10190331; 9618166; 11317356; 11932316; 16570074; 24224479; 26969326; 18285825; 15689455; 15355436). -
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 with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (85 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sulfate permease family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over 10 unrelated individuals with SLC26A4-related conditions in both compound heterozygous and homozygous states (ClinVar, LOVD, PMIDs:11317356, 16570074, 19017801, 19204907, 24224479). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:5
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SLC26A4: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting -
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Published functional studies demonstrate a damaging effect on iodide transport (Taylor et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed multiple times with a different pathogenic variant in unrelated patients with features of Pendred syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Campbell et al., 2001; Blons et al., 2004; Albert et al., 2006; Choi et al., 2009; Ladsous et al., 2014; Soh et al., 2015; Cengiz et al., 2017; Roman et al., 2020); This variant is associated with the following publications: (PMID: 31971949, 31589614, 31980526, 24224479, 14679580, 11932316, 10190331, 10700480, 15355436, 19204907, 10861298, 25741868, 27771369, 25394566, 28964290, 18285825, 11317356, 9618166, 19509082, 16570074, 15689455, 16283880, 32853555, 26969326, 20301640) -
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 209 of the SLC26A4 protein (p.Gly209Val). This variant is present in population databases (rs111033303, gnomAD 0.06%). This missense change has been observed in individuals with Pendred syndrome or deafness (PMID: 9618166, 11317356, 11932316, 16570074, 19204907, 19509082, 21366435, 24224479, 25394566, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4821). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11932316). For these reasons, this variant has been classified as Pathogenic. -
SLC26A4-related disorder Pathogenic:2
The SLC26A4 c.626G>T variant is predicted to result in the amino acid substitution p.Gly209Val. This variant has been reported to be causative for Pendred syndrome (Van Hauwe et al. 1998. PubMed ID: 9618166; Ladsous et al. 2014. PubMed ID: 24224479; Albert et al. 2006. PubMed ID: 16570074; Choi et al. 2009. PubMed ID: 19204907). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
The SLC26A4 c.626G>T (p.Gly209Val) missense variant has been reported in at least eight studies in related and unrelated probands, including one in a homozygous state and 17 in a compound heterozygous state (Van Hauwe et al. 1998; Campbell et al. 2001; Taylor et al. 2002; Pryor et al. 2005; Pera et al. 2008; Ladsous et al. 2014; Soh et al. 2015; Sloan-Heggen et al. 2016). Pera et al. (2008) described two affected siblings who were compound heterozygous for the p.Gly209Val variant and another variant, while their unaffected parents were identified as carriers. The p.Gly209Val variant was absent from 314 controls, but is reported at a frequency of 0.00070 in the European American population of the Exome Sequencing Project. In HeLa cells, the p.Gly209Val variant showed normal cellular localization, but reduced iodide efflux compared to wildtype (Taylor et al. 2002). Based on the collective evidence, this variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Rare genetic deafness Pathogenic:1
The p.Gly209Val variant in SLC26A4 has been reported in at least 15 individuals with hearing loss and EVA (DFNB4) or Pendred syndrome (Van Hauwe 1998, Usami 199 9, Campbell 2001, Pryor 2005, Albert 2006, Pera 2008, LMM data). Many affected i ndividuals were homozygous or compound heterozygous. This variant has been ident ified in 75/126676 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org; dbSNP rs111033303); however, its frequency is low enough to be consistent with a recessive carrier frequency for Pendred s yndrome or nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive DFNB4 or Pendred syndrome b ased on the previously reported biallelic occurrence in multiple affected indivi duals, association with specific clinical features, and a low frequency in the g eneral population. ACMG/AMP Criteria applied: PM3_Strong, PS4, PP4. -
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at