Submissions for variant NM_000112.4(SLC26A2):c.1957T>A (p.Cys653Ser)

gnomAD frequency: 0.00014  dbSNP: rs104893924

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224702	SCV000228778	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224702	SCV000280826	pathogenic	not provided	2014-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000409936	SCV000487415	likely pathogenic	Atelosteogenesis type II	2016-03-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780712	SCV000918219	pathogenic	Sulfate transporter-related osteochondrodysplasia	2018-06-07	criteria provided, single submitter	clinical testing	Variant summary: SLC26A2 c.1957T>A (p.Cys653Ser) 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 0.00013 in 276994 control chromosomes (gnomAD). The variant, c.1957T>A, has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with recessive Multiple epiphyseal dysplasia (Ballhausen_2003, Jackson_2012). These data indicate that the variant is very likely to be associated with disease. A functional study, Karniski_2004, found the variant to have ~55% stimulated sulfate transport. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477884	SCV000952836	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 653 of the SLC26A2 protein (p.Cys653Ser). This variant is present in population databases (rs104893924, gnomAD 0.03%). This missense change has been observed in individuals with diastrophic dysplasia or epiphyseal dysplasia (PMID: 11241838, 12966518, 20525296, 21077204). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4098). 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). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224702	SCV001159701	pathogenic	not provided	2021-02-05	criteria provided, single submitter	clinical testing	The SLC26A2 c.1957T>A; p.Cys653Ser variant (rs104893924) is one of the most frequently found pathogenic SLC26A2 variants and has been described in the homozygous and compound heterozygous states in individuals with recessive multiple epiphyseal dysplasia (rMED) and diastrophic dysplasia (DTD; Czarny-Ratajczak 2010, Hinrichs 2010, Makitie 2003, Rossi 2001). It contains an entry in ClinVar (Variation ID: 4098) and is observed in the European (non-Finnish) population at an overall frequency of 0.027% (35/129008 alleles) in the Genome Aggregation Database. The cysteine at codon 653 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In addition, functional in vitro studies of the variant protein demonstrate reduced protein expression and sulfate transport function when compared to wild type protein (Karniski 2004). Based on available information, this variant is considered pathogenic. REFERENCES Czarny-Ratajczak M et al. New intermediate phenotype between MED and DD caused by compound heterozygous mutations in the DTDST gene. Am J Med Genet A. 2010; 152A(12): 3036-3042. Hinrichs T et al. Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene--phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: case report. BMC Musculoskelet Disord. 2010;11:110. Karniski L. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet. 2004; 13(19): 2165-2171. Makitie O et al. Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign. Am J Med Genet A. 2003;122A(3): 187-192. 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.
Myriad Genetics, Inc.	RCV000055760	SCV001194036	likely pathogenic	Diastrophic dysplasia	2019-12-24	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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.	RCV001030750	SCV001194037	likely pathogenic	3MC syndrome 2	2019-12-24	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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.	RCV000004313	SCV001194038	likely pathogenic	Multiple epiphyseal dysplasia type 4	2019-12-24	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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.	RCV000411019	SCV001194039	likely pathogenic	Achondrogenesis, type IB	2019-12-24	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant 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	RCV000224702	SCV001245892	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SLC26A2: PM3:Very Strong, PM2, PP4, PS3:Supporting
GeneDx	RCV000224702	SCV001814430	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies revealed significantly reduced protein expression in cells with mutant protein, as compared to wild type cells (Karniski et al., 2004); This variant is associated with the following publications: (PMID: 12966518, 30578734, 35026467, 21077204, 20525296, 11241838, 21922596, 11448940, 29724173, 30423444, 29758562, 30462520, 28941661, 30080953, 31980526, 31589614, 33724725, 21155763, 34064542, 33728303, 32633442, 34958143, 34974531, 15294877, 12525546)
Blueprint Genetics	RCV000224702	SCV001832463	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000055760	SCV001934306	likely pathogenic	Diastrophic dysplasia	2020-11-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000224702	SCV002023536	likely pathogenic	not provided	2019-03-22	criteria provided, single submitter	clinical testing
DASA	RCV001813733	SCV002061289	pathogenic	SLC26A2-related disorder	2022-01-05	criteria provided, single submitter	clinical testing	The c.1957T>A;p.(Cys653Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 4098; PMID: 20301524; 11241838; 12966518; 20525296; 21077204; 21922596) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11448940; 15294877) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104893924– gnomAD 0.001249%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Cys653Ser) was detected in trans with a pathogenic variant (PMID: 12966518; 20525296; 21077204; 21922596) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 21077204) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276531	SCV002567002	pathogenic	Connective tissue disorder	2020-03-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000477884	SCV002811593	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2022-03-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411019	SCV004201732	pathogenic	Achondrogenesis, type IB	2024-03-30	criteria provided, single submitter	clinical testing
OMIM	RCV000004313	SCV000024484	pathogenic	Multiple epiphyseal dysplasia type 4	2003-10-15	no assertion criteria provided	literature only
GeneReviews	RCV000055760	SCV000086700	not provided	Diastrophic dysplasia		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477884	SCV000536907	likely pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2016-08-13	no assertion criteria provided	research
Natera, Inc.	RCV000411019	SCV001452796	pathogenic	Achondrogenesis, type IB	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001813733	SCV005352420	pathogenic	SLC26A2-related disorder	2024-03-23	no assertion criteria provided	clinical testing	The SLC26A2 c.1957T>A variant is predicted to result in the amino acid substitution p.Cys653Ser. This variant has been documented to be causative for SLC26A2-related disorders (Makitie et al. 2003. PubMed ID: 12966518; Hinrichs et al. 2010. PubMed ID: 20525296; Czarny-Ratajczak et al. 2010. PubMed ID: 21077204). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.