ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.1151A>G (p.Glu384Gly) (rs111033244)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036425 SCV000060080 pathogenic Rare genetic deafness 2020-09-16 criteria provided, single submitter clinical testing The p.Glu384Gly variant in SLC26A4 has been reported in at least 20 probands with Pendred syndrome or sensorineural hearing loss and segregated in additional affected relatives (Jonard 2010 PMID: 20621367, Coyle 1998 PMID: 9618167, Scott 2000 PMID: 10861298, Dai 2009 PMID: 19509082, Rotman-Pikielny 2002 PMID: 12354788, Borck 2003 PMID: 12788906, Blons 2004 PMID: 15355436, Choi 2009 PMID: 19204907, Cremers 1998 PMID: 9604973, Hutchin 2005 PMID: 16283880, Prasad 2004 PMID: 14679580, Pryor 2005 PMID: 15689455, Shears 2004 PMID: 15099345, Yoon 2008 PMID: 18310264, LMM data). Many of these probands were homozygous or compound heterozygous. It has been identified in 0.022% (28/126362) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033244). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies have shown that the p.Glu384Gly variant protein confers no iodide and chloride transport activity (Scott 2000 PMID: 10861298, Choi 2009 PMID: 19204907). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss or Pendred syndrome based on biallelic occurrences in multiple affected individuals, segregation studies, low frequency in the general population, and functional evidence. ACMG/AMP criteria applied: PM3_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP1, PP4.
GeneDx RCV000520205 SCV000616879 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing The E384G variant has previously been published in the compound heterozygous state in many individual with Pendred syndrome (for examples, see, Coyle et al., 1998; Ladsous et al., 2014; Muskett et al., 2015). Functional studies show E384G significantly damages SLC26A4 function compared to wild-type and localizes this damaged protein to the endoplasmic reticulum of the cell instead of the plasma membrane (Scott et al., 2000; Rotman-Pikielny et al., 2002). This variant is observed in 13/66700 (0.019%) alleles from individuals of European (Non-Finnish) background, in the ExAC dataset (Lek et al., 2016). The E384G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Based on currently available evidence, we consider E384G to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779524 SCV000916171 pathogenic SLC26A4-Related Disorders 2018-08-24 criteria provided, single submitter clinical testing Across a selection of the available literature, the SLC26A4 c.1151A>G (p.Glu384Gly) missense variant has been identified in at least 24 probands with Pendred syndrome or non-syndromic hearing loss, with 16 probands in a compound heterozygous state (with two sib-pairs) and eight probands in a heterozygous state (Coyle et al. 1998; Borck et al. 2003; Blons et al. 2004; Hutchin et al. 2005; Pryor et al. 2005; Dai et al. 2009; Choi et al. 2009; Jonard et al. 2010). Segregation with disease was found in at least one family (Borck et al. 2003). The variant was absent from 415 controls and is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies have shown that the p.Glu384Gly variant protein is consistently located in the intracellular region rather than the plasma membrane and shows decreased Cl-/HCO3- exchange activity (Rotman-Pikielny et al. 2002; Yoon et al. 2008) and an almost complete loss of pendrin-induced iodide and chloride transport activity compared to wild type (Scott et al. 2000; Choi et al. 2009). Based on the collective evidence, the p.Glu384Gly 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 RCV000520205 SCV000964907 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 384 of the SLC26A4 protein (p.Glu384Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs111033244, ExAC 0.02%). This variant has been reported in many individuals affected with Pendred syndrome or nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 9618167, 15355436, 15689455, 16283880, 24224479). ClinVar contains an entry for this variant (Variation ID: 4820). Experimental studies have shown that this missense change causes improper intracellular processing of the SLC26A4 protein, leading to loss of channel transport function (PMID: 10861298, 12354788, 18310264, 22116358). For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000005089 SCV001193962 likely pathogenic Pendred syndrome 2019-11-18 criteria provided, single submitter clinical testing NM_000441.1(SLC26A4):c.1151A>G(E384G) is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 15689455, 9618167, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.1151A>G(E384G) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy populations. Please note: this variant was assessed in the context of healthy population screening.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV001095693 SCV001251501 pathogenic Deafness, autosomal recessive 4, with enlarged vestibular aqueduct criteria provided, single submitter research The SLC26A4 c.1151A>G (p.E384G) variant has been previously reported in multiple individuals with Pendred syndrome or DFNB4 nonsyndromic hearing loss (PMID: 9618167; 15355436; 10861298; 15689455; 16283880; 24224479).
OMIM RCV000005089 SCV000025265 pathogenic Pendred syndrome 2008-07-01 no assertion criteria provided literature only
GeneReviews RCV000005089 SCV000153990 pathogenic Pendred syndrome 2014-05-29 no assertion criteria provided literature only
Natera, Inc. RCV000005089 SCV001455809 pathogenic Pendred syndrome 2020-09-16 no assertion criteria provided clinical testing

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