rs111033307
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.1334T>G(p.Leu445Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,612,682 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L445L) has been classified as Likely benign.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1334T>G | p.Leu445Trp | missense_variant | 11/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1334T>G | p.Leu445Trp | missense_variant | 11/21 | NM_000441.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250764Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135476
GnomAD4 exome AF: 0.000145 AC: 212AN: 1460498Hom.: 0 Cov.: 30 AF XY: 0.000132 AC XY: 96AN XY: 726624
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74360
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:7
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | NM_000441.1(SLC26A4):c.1334T>G(L445W) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18285825, 15355436, 24224479, 9618166, 19204907, 16570074, 20128824 and 23273637. Classification of NM_000441.1(SLC26A4):c.1334T>G(L445W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 leucine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 28 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 sulfate permease (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with either deafness with enlarged vestibular aqueduct (MIM#600791) or Pendred syndrome (MIM#274600) and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 24224479, 26752218). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS ID# 21G002172). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic 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 | Revvity Omics, Revvity | Apr 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2015 | The L445W missense variant has been reported previously in association with Pendred syndrome (Van Hauwe et al., 1998; Choi et al., 2009). In vitro functional studies demonstrated that the presence of the L445W variant resulted in the loss of glycosylation of the pendrin protein (Rebeh et al., 2010). We interpret the L445W variant as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 445 of the SLC26A4 protein (p.Leu445Trp). This variant is present in population databases (rs111033307, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of Pendred syndrome (PMID: 9618166, 19204907, 20128824, 24224479, 26752218). ClinVar contains an entry for this variant (Variation ID: 4829). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19204907, 20128824, 26752218). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Oct 27, 2021 | - - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Affects, no assertion criteria provided | clinical testing;in vitro | National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Aug 20, 2019 | in vitro experiment - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 27, 2010 | The p.Leu445Trp variant has been frequently reported in the literature and is kn own to be associated with the clinical features of DFNB4/Pendred syndrome (Van H auwe 1998, Cama 2009, Choi 2009, Kahrizi 2009, Lopez-Bigas 2001, Masmoudi 2000, Pera 2008, Wilch 2006). Therefore, this variant meets our criteria to be classif ied as pathogenic for DFNB4/Pendred syndrome in an autosomal recessive manner. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at