7-107710132-A-G
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM5PP2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.2168A>G(p.His723Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000653 in 1,609,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H723D) has been classified as 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 13 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SLC26A4 | NM_000441.2 | MANE Select | c.2168A>G | p.His723Arg | missense | Exon 19 of 21 | NP_000432.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SLC26A4 | ENST00000644269.2 | MANE Select | c.2168A>G | p.His723Arg | missense | Exon 19 of 21 | ENSP00000494017.1 | ||
| SLC26A4 | ENST00000644846.1 | n.*70A>G | non_coding_transcript_exon | Exon 8 of 10 | ENSP00000494344.1 | ||||
| SLC26A4 | ENST00000644846.1 | n.*70A>G | 3_prime_UTR | Exon 8 of 10 | ENSP00000494344.1 |
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152254Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000119 AC: 30AN: 251294 AF XY: 0.000103 show subpopulations
GnomAD4 exome AF: 0.0000659 AC: 96AN: 1456722Hom.: 0 Cov.: 28 AF XY: 0.0000662 AC XY: 48AN XY: 725090 show subpopulations
Age Distribution
GnomAD4 genome 0.0000591 AC: 9AN: 152372Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74510 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:10Other:1
Variant summary: SLC26A4 c.2168A>G (p.His723Arg) results in a non-conservative amino acid change located in the STAS domain 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 0.00012 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.2168A>G has been reported in the literature in multiple individuals affected with Pendred Syndrome or hearing loss (e.g. Sagong_2012, Jung_2016). These data indicate that the variant is very likely to be associated with disease. Fifteen 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.
NM_000441.1(SLC26A4):c.2168A>G(H723R) is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 18310264, 24007330, 20826203 and 17718863. Classification of NM_000441.1(SLC26A4):c.2168A>G(H723R) 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.
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 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 (PMID: 20301640). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 32 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) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is prevalent in individuals with Asian descent with Pendred syndrome or deafness 4 with enlarged vestibular aqueduct (ClinVar, PMID: 20301640). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:7
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004825, PMID:9618166, PS1_S).A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000949741, PMID:19040761,24599119, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.958, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000113, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
in vitro experiment
not provided Pathogenic:3
The c.2168A>G; p.His723Arg (rs121908362) is one of commonly observed variants reported in patients with Pendred Syndrome and hearing loss across the Asian population (Van Hauwe, 1998; Ishihara, 2010; Sagong, 2013; Asakura, 2010; Li, 2016). Lee (2014) noted that patients with two copies of the p.His723Arg variant had poorer hearing and higher proportion of incomplete cochlear turns (Mondini structures) compared to compound heterozygotes with a single copy and a different SLC26A4 variant. Cell-based and biochemical experiments further demonstrated that p.His723Arg polypeptides are impaired at reaching the plasma membrane and exhibit abnormal ion exchange activity that can be rescued at low temperature (Yoon, 2008). This variant is listed in the Genome Aggregation Database (gnomAD) in the East Asian population at a frequency of 0.16 percent (identified on 31 out of 18,868 chromosomes with 0 homozygotes) and is reported to the ClinVar database as a pathogenic/likely pathogenic variant (Variation ID: 4825). The histidine at position 723 is highly conserved across 12 species (Alamut v2.9.0), and computational analyses of the effects of the p.His723Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether the p.His723Arg variant is pathogenic.
Published functional studies demonstrate a damaging effect with intracellular retention and decreased protein activity in comparison to wild type (Yoon et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20842945, 19786220, 20583162, 23705809, 25266519, 22884721, 20826203, 23469187, 23755160, 24224479, 9618166, 27176802, 28583500, 27082237, 30693673, 32477112, 31599023, 34943631, 34943614, 11405873, 24007330, 22975760, 11502831, 21961810, 24338212, 26035154, 26100058, 26346818, 27384033, 26763877, 28990112, 28981942, 28786104, 28964290, 27374754, 28802383, 29234782, 28093008, 28052261, 17322586, 30282152, 29447821, 30589569, 30036422, 30733538, 31347505, 30842343, 31564438, 29650690, 31541171, 31827275, 32203226, 30896630, 32425884, 30275481, 32877901, 34170635, 32447495, 15905611, 32459320, 32645618, 32536503, 33597575, 33724713, 34006472, 35204885, 35276235, 35114279, 34801268, 35249537, 34545167, 18310264)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 723 of the SLC26A4 protein (p.His723Arg). This variant is present in population databases (rs121908362, gnomAD 0.2%). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11405873, 17322586, 20583162, 22884721, 23705809, 24338212). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4825). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC26A4 function (PMID: 20583162). For these reasons, this variant has been classified as Pathogenic.
SLC26A4-related disorder Pathogenic:2
The SLC26A4 c.2168A>G (p.His723Arg) missense variant is a common founder variant in both the Japanese and Korean populations (Park et al. 2003). Across a selection of the available literature, it has been identified in a homozygous state in 26 patients, in a compound heterozygous state in 67 patients, and in a heterozygous state in 19 patients, including those with Pendred syndrome and autosomal recessive nonsyndromic hearing loss with enlarged vestibular aqueduct (Tsukamoto et al. 2003; Park et al. 2005; Cho et al. 2006; Kim et al. 2009; Reyes et al. 2009; Miyagawa et al. 2014; Lu et al. 2015; Tsukada et al. 2015). Family studies have demonstrated inheritance of the variant from unaffected heterozygous parents. The p.His723Arg variant was identified in a heterozygous state in three of 1024 Asian control alleles (Park et al. 2003; Yuan et al. 2012; Miyagawa et al. 2014) and is reported at a frequency of 0.00174 in the East Asian population of the Exome Aggregation Consortium. Functional studies in HEK 293 and HeLa cells showed the variant causes the protein to be retained in the endoplasmic reticulum rather than localized to the cell membrane and significantly reduces chloride bicarbonate ion exchange function, consistent with the proposed disease mechanism. The defects were rescued by incubation at low temperature, suggesting they may be due to protein misfolding (Yoon et al. 2008). Based on the collective evidence, the p.His723Arg 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.
The SLC26A4 c.2168A>G variant is predicted to result in the amino acid substitution p.His723Arg. This variant has been reported as homozygous or compound heterozygous in patients with hearing loss and enlarged vestibular aqueduct (EVA) or Pendred syndrome (PS) (Van Hauwe et al. 1998. PubMed ID: 9618166; Huang et al. 2011. PubMed ID: 21961810; Ladsous et al. 2014. PubMed ID: 24224479; Sakuma et al. 2016. PubMed ID: 26763877). Functional studies have shown that the p.His723Arg variant results in abnormal cellular localization and ion transport (Yoon et al. 2008. PubMed ID: 18310264; Ishihara et al. 2010. PubMed ID: 20826203; Lee et al. 2014. PubMed ID: 24007330). This variant is reported in 0.16% of alleles in individuals of East-Asian descent in gnomAD, and is reported to be a common pathogenic variant in this population (Yoon et al. 2008. PubMed ID: 18310264; Lee et al. 2014. PubMed ID: 24007330). This variant is interpreted as pathogenic.
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
For recessive disorders, detected in trans with a pathogenic variant.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).
Rare genetic deafness Pathogenic:1
The p.His723Arg variant in SLC26A4 has been reported in 37 probands with Pendred syndrome (Wu 2005, Van Hauwe 1998, Lee 2008, Asakura 2010, Cho 2006, Dai 2008, Hu 2007, Ishihara 2010, Kim 2009, Park 2003, Reyes 2009, Tsukamoto 2003, Usami 1999, Yoon 2008). Many of these probands were homozygous or compound heterozygous, and the variant has segregated with disease in several families. Furthermore, functional studies revealed that the p.His723Arg variant disrupts the normal cellular localization and ion transport activity of the protein (Yoon 2008, Ishihara 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at