chr5-149980428-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000112.4(SLC26A2):c.835C>T(p.Arg279Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,060 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000112.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00107 AC: 163AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000975 AC: 245AN: 251240Hom.: 0 AF XY: 0.000950 AC XY: 129AN XY: 135782
GnomAD4 exome AF: 0.00146 AC: 2129AN: 1461850Hom.: 5 Cov.: 33 AF XY: 0.00138 AC XY: 1007AN XY: 727230
GnomAD4 genome 0.00107 AC: 163AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83AN XY: 74422
ClinVar
Submissions by phenotype
not provided Pathogenic:10
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Most common pathogenic variant reported in the SLC26A2 gene among non-Finnish European individuals (Bonafe et al., 2014a); Reported as a mild disease-associated variant with phenotypic variability ranging from multiple epiphyseal dysplasia, when seen in the homozygous state, to the more severe diastrophic dysplasia, when seen in a compound heterozygous state (Bonafe et al., 2014a); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10465113, 24598000, 20219950, 24458706, 26354092, 12193993, 20592910, 10482955, 22052783, 9342225, 11241838, 16642506, 27065010, 15316973, 29024831, 28726809, 26990548, 8931695, 30609409, 31028937, 30423444, 31980526, 32510848, 20301493, 15294877, 34426522, 31589614, 32333414, 33726816, 34064542, 33728303, 32633442, 34012376, 8571951, 23840040, 12525546, 33742171) -
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The SLC26A2 c.835C>T; p.Arg279Trp variant (rs104893915) is the second most frequently found SLC26A2 pathogenic variant. It has been described in the homozygous state in numerous individuals with autosomal recessive multiple epiphyseal dysplasia (rMED) with variable presentation including joint pain, hand/foot deformities, scoliosis, reduced stature, brachydactyly, abnormally shaped epiphyses and double layered patella (Ballhausen 2003, Barreda-Bonis 2018, Czarny-Ratajczak 2001, Huber 2001, Rossi 2001, Superti-Furga 1999). It has also been observed in the compound heterozygous state in patients with rMED, diastrophic dysplasia, atelosteogenesis, and in a patient with intermediate phenotype of diastrophic dysplasia/atelosteogenesis (Barreda-Bonis 2018, Hastbacka 1996, Macias-Gomez 2004, Rossi 1996). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 4089), and is observed in the general population at an overall frequency of 0.098% (271/276946 alleles) in the Genome Aggregation Database. Additionally, functional in vitro studies of the variant protein demonstrate reduced protein expression and sulfate transport function, but proper glycosylation and plasma membrane targeting when compared to wild type protein (Karniski 2004). Based on available information, this variant is considered pathogenic. REFERENCES Ballhausen D et al. Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W. J Med Genet 2003; 40:65. Barreda-Bonis A et al. Multiple SLC26A2 mutations occurring in a three-generational family. Eur J Med Genet. 2018 Jan;61(1):24-28. Czarny-Ratajczak M et al. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet 2001; 69:669-80. Hastbacka J et al. Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet 1996; 58(2):255-262. Huber C et al. Sulphate transporter gene mutations in apparently isolated club foot. J Med Genet 2001; 38:191-3. Karniski LP et al. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet 2004; 13(19):2165-2171. Macias-Gomez NM et al. Diastrophic dysplasia and atelosteogenesis type II as expression of compound heterozygosis: first report of a Mexican patient and genotype-phenotype correlation. Am J Med Genet A 2004; 129A(2):190-192. Rossi A et al. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat 2001; 17(3):159-171. Rossi A et al. Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. Hum Genet 1996; 98(6):657-661. Superti-Furga A et al. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. J Med Genet 1999; 36:621-624. -
SLC26A2: PM3:Very Strong, PM2, PS3:Supporting -
Multiple epiphyseal dysplasia type 4 Pathogenic:8
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A known missense variant, c.835C>T (ClinVar variation ID: 4089; Maeda K et al., 2006) in exon 3 of SLC26A2 gene was observed in homozygous state in proband. On segregation, the variant was observed in heterozygous state in her mother and father. This variant is observed in gnomAD (v4.1.0) population database with an allele frequency of 0.001420 (het count: 2292, hom count: 5) and in 3 individuals in heterozygous state in our in-house data of 3455 exomes -
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NM_000112.3(SLC26A2):c.835C>T(R279W) is classified as pathogenic and is associated with recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 8571951, 11565064, 11303514, 12525546, and 9342225. Classification of NM_000112.3(SLC26A2):c.835C>T(R279W) 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. -
This variant is an established disease-causing mutation that has been reported as pathogenic by multiple clinical diagnostic laboratories in ClinVar (Variation ID# 4089). This variant has been reported in the homozygous state in individuals with multiple epiphyseal dysplasia (PMID 20301483, 12525546). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.001% (271/276946) and thus is presumed to be rare. It affects a highly conserved amino acid (up to Tetraodon, considering 12 species) and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.835C>T (p.Arg279Trp) variant is classified as pathogenic. -
Diastrophic dysplasia Pathogenic:5Other:1
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NM_000112.3(SLC26A2):c.835C>T(R279W) is classified as pathogenic and is associated with recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 8571951, 11565064, 11303514, 12525546, and 9342225. Classification of NM_000112.3(SLC26A2):c.835C>T(R279W) 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. -
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -
The p.Arg279Trp (NM_000112.3 c.835C>T) variant in SLC26A2 has been reported in m any homozygous and compound heterozygous individuals with a range of diseases wi thin the diastrophic dysplasia spectrum, and has generally been associated with milder multiple epiphseal dysplasia when it is homozygous or compound heterozygo us with another mild variant, and with more severe diastrophic dysplasia or atel osteogenesis type 2 when it is compound heterozygous with a severe SLC26A2 varia nt (Rossi 1996, Hastaback 1996, Superti-Furga 1999, Huber 2001, Czarny-Ratajczak 2001, Ballhausen 2003, Macias-Gomze 2004, Dwyer 2010, Barbosa 2011, Mattos 2014 , Makitie 2015). This variant has also been reported in ClinVar (Variation ID#40 89) as pathogenic by multiple laboratories. In vitro functional studies provide support that the variant impacts the protein (Karniski 2004, and Heneghan 2010). This variant has been identified in 0.217% (22/10,138) of Ashkenazi Jewish chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute .org; dbSNP rs104893915). Although this variant has been seen in the general pop ulation, its frequency is low enough to be consistent with a recessive carrier f requency. In summary, this variant meets criteria to be classified as pathogenic for diastrophic dysplasia in an autosomal recessive manner based upon its biall elic occurrence in individuals with this disease and the predicted impact on the protein. -
Achondrogenesis, type IB Pathogenic:3
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NM_000112.3(SLC26A2):c.835C>T(R279W) is classified as pathogenic and is associated with recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 8571951, 11565064, 11303514, 12525546, and 9342225. Classification of NM_000112.3(SLC26A2):c.835C>T(R279W) 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. -
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Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:3
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This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 279 of the SLC26A2 protein (p.Arg279Trp). This variant is present in population databases (rs104893915, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with SLC26A2-related disease (PMID: 8571951, 9342225, 10465113, 10482955, 16642506, 21077202, 22052783, 23840040, 27065010). ClinVar contains an entry for this variant (Variation ID: 4089). 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 SLC26A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 15294877, 20219950). For these reasons, this variant has been classified as Pathogenic. -
PM2_Supporting+PP3_Moderate+PM3_VeryStrong+PP4 -
Atelosteogenesis type II Pathogenic:2
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SLC26A2-related disorder Pathogenic:2
The SLC26A2 c.835C>T (p.Arg279Trp) missense variant is well-described in the literature as the most common pathogenic variant in sulfate transporter-related osteochondrodysplasia outside of Finland, accounting for 45% of disease alleles (Bonafé et al. 2013). The p.Arg279Trp variant has been reported in at least nine studies in which it is found in a total of 43 patients with SLC26A2-related disorders including 25 in a homozygous state, 12 in a compound heterozygous state, and six in a heterozygous state where a second variant was not detected (Hästbacka et al. 1996; Rossi et al. 1996; Superti-Furga et al. 1999; Czarny-Ratajczak et al. 2001; Huber et al. 2001; Ballhausen et al. 2003; MacÃas-Gómez et al. 2004; Mattos et al. 2014; Mäkitie et al. 2015). The p.Arg279Trp variant was absent from 120 controls, but is reported at a frequency of 0.00432 in the admixed American population of the 1000 Genomes Project. This allele frequency is high but may be explained by a milder phenotypic presentation. Functional studies in Xenopus oocytes demonstrated that the p.Arg279Trp variant results in reductions of 70% to 80% of the uptake of both sulfate and oxalate compared to wild type, while the surface abundance of the variant protein was similar to wild type levels (Heneghan et al. 2010). The p.Arg279Trp variant is generally considered a mild pathogenic variant. Individuals who are homozygous for the p.Arg279Trp variant have a mild phenotype and are generally diagnosed with multiple epiphyseal dysplasia, but may have some features of diastrophic dysplasia. Some homozygous individuals may also be asymptomatic and remain undiagnosed. A range of phenotypes is seen in individuals who are compound heterozygous for the p.Arg279Trp variant and another missense variant or the well-described Finnish variant in the 5' UTR. The majority of these cases fall into the diastrophic dysplasia category, but can also be more severe or milder. Individuals who are compound heterozygous for the p.Arg279Trp variant and a premature stop-gained variant usually present with atelosteogenesis or sometimes with diastrophic dysplasia. Thus far, the p.Arg279Trp variant has not been associated with any cases of achondrogenesis, which is the most severe disease in the spectrum. Based on the collective evidence, the p.Arg279Trp is classified as pathogenic for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
The SLC26A2 c.835C>T variant is predicted to result in the amino acid substitution p.Arg279Trp. This variant has been reported to be causative for diastrophic dysplasia (Hastbacka et al. 1999. PubMed ID: 10482955; Hastbacka et al. 1996. PubMed ID: 8571951), for mild recessive multiple epiphyseal dysplasia (Lacassie et al. 2011. PubMed ID: 22052783), and for diastrophic dysplasia/multiple epiphyseal dysplasia (Zechi-Ceide et al. 2013. PubMed ID: 23840040). This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4089). Given the evidence, we interpret c.835C>T (p.Arg279Trp) as pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.835C>T (p.R279W) alteration is located in exon 3 (coding exon 2) of the SLC26A2 gene. This alteration results from a C to T substitution at nucleotide position 835, causing the arginine (R) at amino acid position 279 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.096% (271/282628) total alleles studied. The highest observed frequency was 0.222% (23/10358) of Ashkenazi Jewish alleles. The p.R279W alteration has been observed homozygous or compound heterozygous in individuals presenting with various disorders including multiple epiphyseal dysplasia (rMED), diastrophic dysplasia (DTD), and atelosteogenesis type II. This alteration is the most common in the European, Non-Finnish population (Superti-Furga, 1999; Rossi, 2001). Patients who are homozygous for this alteration typically have a clinical diagnosis of multiple epiphyseal dysplasia (Ballhausen, 2003) Other patients in which the p.R279W alteration occurs in trans with a second mutation can have atelosteogenesis type II (Hastback, 1996), diastrophic dysplasia (Rossi, 2001), or intermediate syndromes involving various features of these disorders (Zechi-Ceide, 2013; Maeda, 2006). This amino acid position is highly conserved in available vertebrate species. The p.R279 amino acid is located in the sulfate transporter family protein domain (Rossi, 2001). Functional analysis demonstrated that the p.R279W alteration decreased protein function (~45% of wildtype) (Karniski, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Sulfate transporter-related osteochondrodysplasia Pathogenic:1
Variant summary: The SLC26A2 c.835C>T (p.Arg279Trp) variant involves the alteration of a conserved nucleotide resulting in a replacement of a large size and basic Arginine (R) with a large size and aromatic Tryptophan (W) located in the sulphate transferase domain. 4/4 in silico tools predict a damaging outcome for this substitution. This variant was found in 97/121378 control chromosomes at a frequency of 0.0007992, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC26A2 variant (0.002958). It was reported in several non-lethal SLC26A2-related dysplasia patients in either homozygosity or in compound heterozygosity with other pathogenic mutations indicating pathogenicity. Additionally, independent functional studies demonstrated the variant to impair sulphate and oxalate transport activity of SLC26A2 further supporting a deleterious impact. In addition, the variant is known as one of the most common pathogenic SLC26A2 (GeneReviews). Considering all evidence, the variant was classified as Pathogenic. -
3MC syndrome 2 Pathogenic:1
NM_000112.3(SLC26A2):c.835C>T(R279W) is classified as pathogenic and is associated with recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 8571951, 11565064, 11303514, 12525546, and 9342225. Classification of NM_000112.3(SLC26A2):c.835C>T(R279W) 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. -
Connective tissue disorder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at