rs111033205
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4
The NM_000441.2(SLC26A4):āc.85G>Cā(p.Glu29Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,557,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E29D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.85G>C | p.Glu29Gln | missense_variant | 2/21 | ENST00000644269.2 | |
SLC26A4-AS1 | NR_028137.1 | n.73C>G | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.85G>C | p.Glu29Gln | missense_variant | 2/21 | NM_000441.2 | P1 | ||
SLC26A4-AS1 | ENST00000668981.1 | n.133C>G | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000926 AC: 15AN: 162000Hom.: 0 AF XY: 0.0000572 AC XY: 5AN XY: 87366
GnomAD4 exome AF: 0.000158 AC: 222AN: 1405620Hom.: 0 Cov.: 30 AF XY: 0.000163 AC XY: 113AN XY: 694860
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74378
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | Published functional studies demonstrate a damaging effect due to reduced iodide transport activity (Pera et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14679580, 29372807, 24224479, 11317356, 15099345, 15355436, 16950989, 18285825, 20597900, 23336812, 17503324, 19017801, 16570074, 31589614, 34426522, 34170635, 33199029, 31541171, 36499699) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 11, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 16, 2022 | PM2_supporting, PM3_very_strong, PS3_supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 29 of the SLC26A4 protein (p.Glu29Gln). This variant is present in population databases (rs111033205, gnomAD 0.03%). This missense change has been observed in individuals with SLC26A4-related conditions (PMID: 11317356, 15355436, 16570074, 20597900, 25394566). ClinVar contains an entry for this variant (Variation ID: 4839). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19017801). This variant disrupts the p.Glu29 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC26A4-related conditions (PMID: 22285650, 25372295), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | The Shared Resource Centre "Genome", Research Centre for Medical Genetics | Nov 10, 2022 | - - |
Likely pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
Pendred syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 09, 2019 | - - |
Wolff-Parkinson-White pattern Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Jul 14, 2017 | This variant was identified in an individual with Wolff-Parkinson-White syndrome - |
SLC26A4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 24, 2018 | Across a selection of the available literature, the SLC26A4 c.85G>C (p.Glu29Gln) missense variant has been reported in at least nine studies in which it was identified in a total of 18 individuals, including in a compound heterozygous state in 14 individuals, in a heterozygous state in three individuals, in a double heterozygous state in one individual and in one individual with unknown zygosity. Affected individuals were diagnosed with either Pendred syndrome, an autosomal recessive form of deafness, or enlarged vestibular aqueduct or Mondini dysplasia (Campbell et al. 2001; Prasad et al. 2004; Blons et al. 2004; Alberts et al. 2006; Yang et al. 2007; Pera et al. 2008; Pourova et al. 2010; Rendtorff et al. 2013; Ladous et al. 2014). The p.Glu29Gln variant was found to segregate in at least one study (Yang et al. 2007). The variant was absent from 469 controls and is reported at a frequency of 0.000229 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using fluorimetric measurements showed that the p.Glu29Gln variant protein has reduced chloride/iodide transport (Pera et al. 2008). Based on the collective evidence, the p.Glu29Gln 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. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 14, 2015 | The p.Glu29Gln variant in SLC26A4 has been identified in multiple individuals wi th hearing loss and temporal bone abnormalities including over 15 probands who w ere compound heterozygous with another pathogenic variant in SLC26A4, and it has segregated in three affected siblings (Albert 2006, Campbell 2001, Gardner 2006 , Ladsous 2014, Pera 2008, Pourova 2010, Rendtorff 2013, LMM unpublished data). Functional studies have demonstrated that this variant impacts the protein func tion (Pera 2008). In summary, this variant meets our criteria to be classified as pathogenic for DFNB4 nonsyndromic hearing loss or Pendred syndrome in an auto somal recessive manner. - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 11, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at