ClinVar Miner

Submissions for variant NM_000441.1(SLC26A4):c.349C>T (rs145254330)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757776 SCV000886130 uncertain significance not provided 2017-07-30 criteria provided, single submitter clinical testing The p.Leu117Phe variant (rs145254330) has been reported in multiple individuals with non-syndromic hearing loss (Reardon 2000, Albert 2006, Sloan-Heggen 2016); however, it has never been observed in trans with any pathogenic allele, and functional studies revealed no difference in protein localization or channel function when compared to wild-type SLC26A4 protein (Taylor 2002). Furthermore, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.51% (identified in 52 out of 10,150 chromosomes), and is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 43555). Taken together, the clinical significance of the p.Leu117Phe variant cannot be determined with certainty.
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000225040 SCV000840507 likely pathogenic Pendred syndrome 2018-09-26 reviewed by expert panel curation This variant has been detected in 4 patients with hearing loss in trans with p.Val570Ile, p.Thr416Pro, c.-4+1>C and p.Thr193Ile (PM3_VeryStrong; Partners LMM unpublished internal data, PMID: 26969326, Karen Avraham Lab internal data SCV000282015.2). Of note, the variant has also been observed in heterozygosity in two individuals with enlarged vestibular aqueduct, in which a second allele was not identified (PMID: 16570074, 10700480), however, this is not uncommon for patients with hearing loss due to SLC26A4. The p.Leu117Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 5 affected and 4 unaffected family members, across 2 Ashkenazi Jewish families with hearing loss (PP1_Strong; Karen Avraham Lab internal data SCV000282016.1, SCV000282017.1). At least four probands with the p.Leu117Phe variant in compound heterozygosity with a second pathogenic or suspected-pathogenic SLC26A4 variant displayed features of EVA (PP4; Partners LMM unpublished internal data, PMID: 26969326). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). A functional study demonstrated that this variant may not impact localization or the iodide efflux capacity (BS3_Supporting; PMID: 27771369, 11932316), however, the functional may not assess all ion transport functions of the protein and/or ensure that the assay reflects the true biological environment and therefore the ClinGen Hearing Loss Expert Panel (HL EP) chose not to consider this evidence fully in conflict with the pathogenic evidence. The filtering allele frequency of the p.Leu117Phe variant in the SLC26A4 gene is 0.4% for Ashkenazi Jewish chromosomes by the Genome Aggregation Database (52/10150 with 95% CI) based on thresholds defined by the ClinGen HL EP for autosomal recessive Pendred syndrome variants (BS1). However, given the lack of understanding of Pendred syndrome prevalence in the Ashkenazi Jewish population and the finding that a study of ~10,000 Jewish hearing individuals detected no homozygotes (Karen Avraham Lab internal data SCV000282015.2) this allele frequency was not considered strong enough conflicting evidence to counter the pathogenic evidence. In summary, this variant has been classified as likely pathogenic for autosomal recessive Pendred syndrome based on the full set of evidence described above. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PP1_Strong, PP4, PP3, BS1, BS3_Supporting.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036491 SCV000060146 likely pathogenic Rare genetic deafness 2017-01-12 criteria provided, single submitter clinical testing The p.Leu117Phe variant in SLC26A4 has been previously reported in 8 individuals with hearing loss, 6 of whom had enlarged vestibular aqueducts, and 5 of whom h ad a second SLC26A4 variant on the remaining allele (Reardon 2000, Albert 2006, Sloan-Heggen 2016, ClinVar SCV000282015.1, LMM unpublished data). This variant is also present in 0.5% (52/10160) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1452543 30); however, this frequency is low enough to be consistent with a recessive car rier frequency. An in vitro functional study demonstrated that the variant did n ot impact localization of the protein to the cell membrane or iodide efflux capa city; however, not all ion transport functions of the mutant proteins were asses sed (Taylor 2002). In addition, the leucine (Leu) residue at position 117 is hig hly conserved across mammals and distant species, suggesting that variants at th is position are not tolerated. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Leu117Phe variant is lik ely pathogenic.
Laboratory of Prof. Karen Avraham,Tel Aviv University RCV000225040 SCV000282016 pathogenic Pendred syndrome 2016-02-19 no assertion criteria provided research Congenital, profound HL
Laboratory of Prof. Karen Avraham,Tel Aviv University RCV000225082 SCV000282017 pathogenic Enlarged vestibular aqueduct 2016-02-19 no assertion criteria provided research Congenital, profound HL

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