chr7-107689130-C-T
Variant summary
Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.1079C>T(p.Ala360Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 4Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- Pendred syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- athyreosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- thyroid hypoplasiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74282 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:3
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3
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not provided Pathogenic:3
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 360 of the SLC26A4 protein (p.Ala360Val). This variant is present in population databases (rs786204474, gnomAD 0.06%). This missense change has been observed in individual(s) with hearing loss (PMID: 17697873, 21961810, 23838540, 26252218, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188793). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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Published functional studies demonstrate this variant impairs SLC26A4 protein localization and function (Yuan et al., 2012); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30842343, 23185506, 26969326, 23838540, 21154317, 17697873, 21961810, 26252218, 27771369, 30275481, 31541171, 24612839, 24341454, 23151025, 33199029, 32447495, 36362242, 35982127, 34416374, 33907123, 32658404) -
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
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PM2_Supporting+PP3+PM3_VeryStrong -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at