ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.2048T>C (p.Phe683Ser)

gnomAD frequency: 0.00001  dbSNP: rs1060499808
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
King Laboratory, University of Washington RCV001004649 SCV002059890 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2020-08-01 criteria provided, single submitter research SLC26A4 c.2048T>C, p.F683S alters a residue completely conserved in all sequenced vertebrates. The vaariant was previously shown to be defective in ion transport (PMID: 31599023). The variant is homozygous in 6 children from 2 Palestinian families with pre-lingual moderate hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and present in 2/225902 alleles on gnomAD, both heterozygotes.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000454307 SCV002768991 pathogenic Pendred syndrome 2022-02-02 criteria provided, single submitter clinical testing 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 phenylalanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 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 STAS domain (DECIPHER, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been identified at least two individuals with deafness with enlarged vestibular aqueduct (MIM#600791) and hearing loss. It was noted that one of them had an unknown second allele (PMID: 21366435, 30622556). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated impaired ion transport and cellular mislocalisation (PMID: 31599023). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000454307 SCV002819465 pathogenic Pendred syndrome 2022-12-12 criteria provided, single submitter clinical testing Variant summary: SLC26A4 c.2048T>C (p.Phe683Ser) results in a non-conservative amino acid change located in the STAS domain (IPR002645) 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 8.9e-06 in 225902 control chromosomes. c.2048T>C has been reported in the literature as bialleic homozygous or compound heterozygous genotypes in multiple individuals affected with features of Pendred Syndrome (example, Morgan_2018, Smits_2022, Abu Rayyan_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002522746 SCV003440714 pathogenic not provided 2022-10-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 31599023). 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. ClinVar contains an entry for this variant (Variation ID: 402277). This missense change has been observed in individuals with hearing loss (PMID: 30622556, 32747562). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 683 of the SLC26A4 protein (p.Phe683Ser).
Baylor Genetics RCV001004649 SCV004204238 likely pathogenic Autosomal recessive nonsyndromic hearing loss 4 2024-03-27 criteria provided, single submitter clinical testing
Hereditary Research Laboratory, Bethlehem University RCV000454307 SCV000538121 pathogenic Pendred syndrome 2016-06-04 no assertion criteria provided research congenital, moderate, Pendred signs?
National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center RCV001004649 SCV000994905 affects Autosomal recessive nonsyndromic hearing loss 4 2019-08-20 no assertion criteria provided literature only in vitro experiment

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