rs111033244
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):āc.1151A>Gā(p.Glu384Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 1,577,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000441.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1151A>G | p.Glu384Gly | missense_variant, splice_region_variant | 10/21 | ENST00000644269.2 | NP_000432.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1151A>G | p.Glu384Gly | missense_variant, splice_region_variant | 10/21 | NM_000441.2 | ENSP00000494017 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000108 AC: 27AN: 251090Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135682
GnomAD4 exome AF: 0.000373 AC: 532AN: 1425244Hom.: 0 Cov.: 27 AF XY: 0.000360 AC XY: 256AN XY: 711362
GnomAD4 genome AF: 0.000151 AC: 23AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74328
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2022 | Variant summary: SLC26A4 c.1151A>G (p.Glu384Gly) results in a non-conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251090 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.1151A>G has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with features of Pendred Syndrome/Syndromic Sensorineural Hearing Loss (SNHL)/Non-syndromic SNHL (example, Coyle_1998, Hutchin_2005, Molina-Ramirez_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete loss of Pendrin induced chloride and iodide transport (Scott_2000) and complete retention of Pendrin in the endoplasmic reticulum (ER) as a major mechanism for Pendred syndrome (Rotman-Pikielny_2002). Eight 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 18, 2019 | NM_000441.1(SLC26A4):c.1151A>G(E384G) is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 15689455, 9618167, 18310264 and 12354788. Classification of NM_000441.1(SLC26A4):c.1151A>G(E384G) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 384 of the SLC26A4 protein (p.Glu384Gly). This variant is present in population databases (rs111033244, gnomAD 0.02%). This missense change has been observed in individuals with Pendred syndrome or nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 9618167, 15355436, 15689455, 16283880, 24224479). ClinVar contains an entry for this variant (Variation ID: 4820). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 10861298, 12354788, 18310264, 22116358). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 10, 2022 | PP3, PM2_supporting, PM3_very_strong, PS3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2024 | Published functional studies demonstrate a damaging effect due to aberrant protein processing, with retention of pendrin in the endoplasmic reticulum and absence of proper pendrin assembly at the cell membrane as well as impaired protein glycosylation (PMID: 10861298, 18310264, 12354788); 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: 14508505, 21455268, 26485571, 11317356, 14679580, 20553101, 24224479, 19620588, 34416374, 31589614, 32853555, 33879512, 31980526, 22975760, 12354788, 18310264, 24860705, 23824432, 19017801, 25290043, 18368581, 18250610, 15368487, 25455162, 22116358, 20739942, 9604973, 9618167, 23336812, 15355436, 12788906, 21917135, 17672986, 23838540, 20621367, 23504402, 23965030, 15689455, 19204907, 11919333, 16283880, 15099345, 19509082, 20301640, 27771369, 34171171, 10861298, 38474007) - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The SLC26A4 c.1151A>G (p.E384G) variant has been previously reported in multiple individuals with Pendred syndrome or DFNB4 nonsyndromic hearing loss (PMID: 9618167; 15355436; 10861298; 15689455; 16283880; 24224479). - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine (exon 10). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (30 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (sulfate transporter domain; PDB, NCBI). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in patients with hearing loss with enlarged vestibular aqueduct or Pendred syndrome (ClinVar, PMIDs: 26485571, 19204907, 9618167). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies showed the mutant protein was retained in the endoplasmic reticulum in human COS7 cells (PMID:12354788). The iodide and chloride uptake was lost in Xenopus oocytes containing the mutant cRNA. (PMID:10861298). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
SLC26A4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2018 | Across a selection of the available literature, the SLC26A4 c.1151A>G (p.Glu384Gly) missense variant has been identified in at least 24 probands with Pendred syndrome or non-syndromic hearing loss, with 16 probands in a compound heterozygous state (with two sib-pairs) and eight probands in a heterozygous state (Coyle et al. 1998; Borck et al. 2003; Blons et al. 2004; Hutchin et al. 2005; Pryor et al. 2005; Dai et al. 2009; Choi et al. 2009; Jonard et al. 2010). Segregation with disease was found in at least one family (Borck et al. 2003). The variant was absent from 415 controls and is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional studies have shown that the p.Glu384Gly variant protein is consistently located in the intracellular region rather than the plasma membrane and shows decreased Cl-/HCO3- exchange activity (Rotman-Pikielny et al. 2002; Yoon et al. 2008) and an almost complete loss of pendrin-induced iodide and chloride transport activity compared to wild type (Scott et al. 2000; Choi et al. 2009). Based on the collective evidence, the p.Glu384Gly 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 16, 2020 | The p.Glu384Gly variant in SLC26A4 has been reported in at least 20 probands with Pendred syndrome or sensorineural hearing loss and segregated in additional affected relatives (Jonard 2010 PMID: 20621367, Coyle 1998 PMID: 9618167, Scott 2000 PMID: 10861298, Dai 2009 PMID: 19509082, Rotman-Pikielny 2002 PMID: 12354788, Borck 2003 PMID: 12788906, Blons 2004 PMID: 15355436, Choi 2009 PMID: 19204907, Cremers 1998 PMID: 9604973, Hutchin 2005 PMID: 16283880, Prasad 2004 PMID: 14679580, Pryor 2005 PMID: 15689455, Shears 2004 PMID: 15099345, Yoon 2008 PMID: 18310264, LMM data). Many of these probands were homozygous or compound heterozygous. It has been identified in 0.022% (28/126362) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033244). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies have shown that the p.Glu384Gly variant protein confers no iodide and chloride transport activity (Scott 2000 PMID: 10861298, Choi 2009 PMID: 19204907). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss or Pendred syndrome based on biallelic occurrences in multiple affected individuals, segregation studies, low frequency in the general population, and functional evidence. ACMG/AMP criteria applied: PM3_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP1, PP4. - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at