Submissions for variant NM_000112.4(SLC26A2):c.835C>T (p.Arg279Trp)

gnomAD frequency: 0.00106  dbSNP: rs104893915

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000266165	SCV000228776	pathogenic	not provided	2018-06-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000266165	SCV000329646	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000275762	SCV000454776	pathogenic	SLC26A2-related disorder	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586600	SCV000695420	pathogenic	Sulfate transporter-related 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.
Laboratory for Molecular Medicine, Mass General Brigham 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.
Ambry Genetics	RCV000624686	SCV000741996	pathogenic	Inborn genetic diseases	2023-06-09	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641290	SCV000762931	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2024-01-31	criteria provided, single submitter	clinical testing	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). 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 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999764	SCV000884514	pathogenic	not specified	2018-07-31	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000641290	SCV000893695	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2021-10-08	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000004307	SCV000996158	pathogenic	Multiple epiphyseal dysplasia type 4	2018-06-13	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000004305	SCV001162984	pathogenic	Atelosteogenesis type II	2022-07-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000004307	SCV001193827	pathogenic	Multiple epiphyseal dysplasia type 4	2019-11-18	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000004306	SCV001194187	pathogenic	Diastrophic dysplasia	2019-11-18	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV001030752	SCV001194188	pathogenic	Achondrogenesis, type IB	2019-11-18	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV001030753	SCV001194189	pathogenic	3MC syndrome 2	2019-11-18	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000266165	SCV001245891	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	SLC26A2: PM3:Very Strong, PM2, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000004307	SCV001428980	pathogenic	Multiple epiphyseal dysplasia type 4	2017-10-11	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000004307	SCV001439304	pathogenic	Multiple epiphyseal dysplasia type 4	2020-07-06	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000266165	SCV001762099	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000266165	SCV001832508	pathogenic	not provided	2020-02-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000266165	SCV002020665	pathogenic	not provided	2020-01-28	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000004307	SCV002053884	likely pathogenic	Multiple epiphyseal dysplasia type 4		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276530	SCV002567008	pathogenic	Connective tissue disorder	2021-08-18	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000004306	SCV003808082	pathogenic	Diastrophic dysplasia	2022-12-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Baylor Genetics	RCV000004307	SCV003835304	pathogenic	Multiple epiphyseal dysplasia type 4	2022-07-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004306	SCV003835343	pathogenic	Diastrophic dysplasia	2022-07-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001030752	SCV003836388	pathogenic	Achondrogenesis, type IB	2024-03-30	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000004307	SCV005051969	pathogenic	Multiple epiphyseal dysplasia type 4	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000004305	SCV000024472	pathogenic	Atelosteogenesis type II	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 type 4	2004-08-30	no assertion criteria provided	literature only
GeneReviews	RCV000004306	SCV000086704	not provided	Diastrophic dysplasia		no assertion provided	literature only
Natera, Inc.	RCV001030752	SCV001452792	pathogenic	Achondrogenesis, type IB	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000266165	SCV001956625	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000266165	SCV001964445	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000266165	SCV002036740	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000275762	SCV005361352	pathogenic	SLC26A2-related disorder	2024-09-10	no assertion criteria provided	clinical testing	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.