ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.626G>T (p.Gly209Val) (rs111033303)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824764 SCV000060156 pathogenic Rare genetic deafness 2017-05-11 criteria provided, single submitter clinical testing 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.
GeneDx RCV000308471 SCV000329518 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The G209V missense variant in the SLC26A4 gene has been reported previously in association with Pendred syndrome (for examples, see Van Hauwe et al., 1998; Taylor et al., 2002; Pera et al., 2008). Functional studies show G209V retains normal cell membrane localization; however, its ability to transport iodide was significantly reduced (Taylor et al., 2002). The G209V variant is observed in 75/126676 (0.0592%) alleles from individuals of European (Non-Finnish) background, in large population cohorts (Lek et al., 2016). The G209V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G209E), as well as a nearby residue (G204V) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider G209V to be a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000308471 SCV000343638 pathogenic not provided 2017-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000344627 SCV000678066 pathogenic Pendred syndrome 2015-10-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000036501 SCV000894403 pathogenic Enlarged vestibular aqueduct; Pendred syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778811 SCV000915191 pathogenic SLC26A4-Related Disorders 2018-10-23 criteria provided, single submitter clinical testing 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.
Invitae RCV000308471 SCV000960084 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 209 of the SLC26A4 protein (p.Gly209Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs111033303, ExAC 0.04%). This variant has been observed to segregate with Pendred syndrome in a family (PMID: 24224479) and it has been observed to be homozygous or in combination with another SLC26A4 variant in individuals affected with Pendred syndrome or deafness (PMID: 24224479, 11317356, 16570074) and in individuals with clinical features of these conditions (PMID: 9618166, 11932316, 26969326, 25394566, 19204907, 21366435, 19509082). ClinVar contains an entry for this variant (Variation ID: 4821). Experimental studies have shown that this missense change disrupts SLC26A4 channel function (PMID: 11932316). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005090 SCV000025266 pathogenic Enlarged vestibular aqueduct 1999-02-01 no assertion criteria provided literature only

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