ClinVar Miner

Submissions for variant NM_000112.3(SLC26A2):c.835C>T (p.Arg279Trp) (rs104893915)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000266165 SCV000884514 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624686 SCV000741996 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000004307 SCV000677900 pathogenic Multiple epiphyseal dysplasia 4 2015-06-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000266165 SCV000228776 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000641290 SCV000893695 pathogenic Achondrogenesis, type IB; Atelosteogenesis type 2; Multiple epiphyseal dysplasia 4; Diastrophic dysplasia 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000266165 SCV000329646 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing The R279W variant in the SLC26A2 gene is the most common pathogenic variant reported in the SLC26A2 gene among non-Finnish European individuals (Bonafé et al., 2014) and is observed in the heterozygous state in the ExAC dataset in 87/66718 (0.13%) alleles from individuals of non-Finnish European background (Lek et al., 2016). The R279W variant is considered 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 (Bonafé et al., 2014). The R279W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro functional studies indicate this variant impairs sulfate transport function (Karniski et al., 2004). We interpret R279W as a pathogenic variant.
GeneReviews RCV000004306 SCV000086704 pathologic Diastrophic dysplasia 2013-07-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000275762 SCV000454776 pathogenic SLC26A2-Related Disorders 2016-08-19 criteria provided, single submitter clinical testing 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; Macías-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.
Integrated Genetics/Laboratory Corporation of America RCV000586600 SCV000695420 pathogenic Osteochondrodysplasia 2016-07-21 criteria provided, single submitter clinical testing 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.
Invitae RCV000641290 SCV000762931 pathogenic Achondrogenesis, type IB; Atelosteogenesis type 2; Multiple epiphyseal dysplasia 4; Diastrophic dysplasia 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 279 of the SLC26A2 protein (p.Arg279Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs104893915, ExAC 0.1%). This variant has been reported as homozygous or in combination with other SLC26A2 variants in individuals affected with SLC26A2-related disease (PMID: 8571951, 9342225, 10465113, 10482955, 16642506, 21077202, 22052783, 23840040, 27065010). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 4089). Experimental studies have shown that this missense impairs SLC26A2-mediated sulfur uptake in vitro (PMID: 15294877, 20219950). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000004306 SCV000731821 pathogenic Diastrophic dysplasia 2018-01-31 criteria provided, single submitter clinical testing 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.
OMIM RCV000004305 SCV000024472 pathogenic Atelosteogenesis type 2 2004-08-30 no assertion criteria provided literature only
OMIM RCV000004306 SCV000024473 pathogenic Diastrophic dysplasia 2004-08-30 no assertion criteria provided literature only
OMIM RCV000004307 SCV000024474 pathogenic Multiple epiphyseal dysplasia 4 2004-08-30 no assertion criteria provided literature only

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