Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
King Laboratory, |
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, |
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, |
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 |
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, |
RCV000454307 | SCV000538121 | pathogenic | Pendred syndrome | 2016-06-04 | no assertion criteria provided | research | congenital, moderate, Pendred signs? |
National Institute of Sensory Organs, |
RCV001004649 | SCV000994905 | affects | Autosomal recessive nonsyndromic hearing loss 4 | 2019-08-20 | no assertion criteria provided | literature only | in vitro experiment |