chr5-149981550-T-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000112.4(SLC26A2):c.1957T>A(p.Cys653Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
SLC26A2
NM_000112.4 missense
NM_000112.4 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.94
Genes affected
SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a domain STAS (size 151) in uniprot entity S26A2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000112.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant 5-149981550-T-A is Pathogenic according to our data. Variant chr5-149981550-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149981550-T-A is described in Lovd as [Likely_pathogenic]. Variant chr5-149981550-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251278Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135808
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GnomAD4 exome AF: 0.000111 AC: 162AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.000132 AC XY: 96AN XY: 727224
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GnomAD4 genome 0.000125 AC: 19AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74318
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2023 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | SLC26A2: PM3:Very Strong, PM2, PP4, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 02, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 22, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 05, 2021 | 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. - |
Achondrogenesis, type IB Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2025 | 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). 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). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Aug 13, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 08, 2024 | - - |
Diastrophic dysplasia Pathogenic:2Other:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 09, 2020 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
SLC26A2-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 23, 2024 | 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. - |
Multiple epiphyseal dysplasia type 4 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2003 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | 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. - |
Atelosteogenesis type II Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 11, 2016 | - - |
Sulfate transporter-related osteochondrodysplasia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2018 | 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. - |
3MC syndrome 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | 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. - |
Connective tissue disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at I651 (P = 0.1057);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at