Submissions for variant NM_000112.4(SLC26A2):c.-26+2T>C

gnomAD frequency: 0.00055  dbSNP: rs386833492

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724163	SCV000700732	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763135	SCV000893694	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2022-05-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779466	SCV000916094	pathogenic	SLC26A2-related disorder	2018-10-10	criteria provided, single submitter	clinical testing	The SLC26A2 c.-26+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product.This variant, which has been described as a founder variant in the Finnish population, has been reported in at least six studies and is found in a total of at least 101 probands including 70 in a homozygous state, 17 in a compound heterozygous state, and 14 in a heterozygous state (Hästbacka et al. 1999; Bonafé et al. 2008; Dwyer et al. 2010; Jackson et al. 2012; Zechi-Ceide et al. 2013; Mäkitie et al. 2015). Of the 101 probands, 77 probands were affected by diastrophic dysplasia, six probands with recessively inherited multiple epiphyseal dysplasia, three probands with a phenotype that was intermediate between diastrophic dysplasia and multiple epiphyseal dysplasia, and one proband with atelosteogenesis. No probands were reported with achondrogenesis or sulfate transporter-related osteochondrodysplasia. The c.-26+2T>C variant is present in at least four unaffected parents in a heterozygous state (Bonafé et al. 2008; Dwyer et al. 2010). The variant was absent from 200 control samples and is reported at a frequency of 0.01515 in the Finnish population of the 1000 Genomes Project. RT-PCR assays using skin fibroblasts from probands homozygous for the c.-26+2T>C variant showed a 5% level of wild type mRNA which was correctly spliced (Hästbacka et al. 1999). Based on the collective evidence, the c.-26+2T>C variant 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	RCV000780711	SCV000918218	pathogenic	Sulfate transporter-related osteochondrodysplasia	2018-02-19	criteria provided, single submitter	clinical testing	Variant summary: SLC26A2 c.-26+2T>C is located in a canonical splice-site in the 5'UTR and is predicted to affect mRNA splicing, resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. This is supported by at least one publication that reports a near complete loss of properly spliced mRNA from patient fibroblasts (Hastbacka_1999). The variant allele was found at a frequency of 0.0014 in 30678 control chromosomes (gnomAD), which does not exceed the maximal expected frequency for a pathogenic variant in the SLC26A2 gene. The c.-26+2T>C variant has been reported in the literature in numerous individuals affected with Sulfate Transporter-Related Osteochondrodysplasia as a homozygous and compound heterozygous allele, and is referred to in the literature as a founder mutation in the Finnish population (Hastbacka_1999). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, though several submitters prior to 2014 classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000991163	SCV001162983	pathogenic	Atelosteogenesis type II	2021-04-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001030744	SCV001193769	pathogenic	Achondrogenesis, type IB	2019-12-26	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C 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.	RCV001030745	SCV001193770	pathogenic	3MC syndrome 2	2019-12-26	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C 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.	RCV000597319	SCV001193771	pathogenic	Multiple epiphyseal dysplasia type 4	2019-12-26	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C 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.	RCV000004312	SCV001194133	pathogenic	Diastrophic dysplasia	2019-12-26	criteria provided, single submitter	clinical testing	NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763135	SCV001220198	pathogenic	Achondrogenesis, type IB; Atelosteogenesis type II; Multiple epiphyseal dysplasia type 4; Diastrophic dysplasia	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the SLC26A2 gene. It does not directly change the encoded amino acid sequence of the SLC26A2 protein. This variant is present in population databases (rs386833492, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with SLC26A2-related diseases in affected families (PMID: 10482955, 21077202, 23840040). It is commonly reported in individuals of Finnish ancestry (PMID: 10482955, 21077202, 23840040). ClinVar contains an entry for this variant (Variation ID: 4097). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000724163	SCV003821108	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001030744	SCV003834895	pathogenic	Achondrogenesis, type IB	2024-03-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004312	SCV003834925	pathogenic	Diastrophic dysplasia	2021-04-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000597319	SCV003835426	pathogenic	Multiple epiphyseal dysplasia type 4	2021-04-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724163	SCV004032635	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SLC26A2: PM3:Very Strong, PM1, PM2, PP4
OMIM	RCV000004312	SCV000024483	pathogenic	Diastrophic dysplasia	2008-12-01	no assertion criteria provided	literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000004312	SCV000081853	pathogenic	Diastrophic dysplasia		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
GeneReviews	RCV000004312	SCV000086695	not provided	Diastrophic dysplasia		no assertion provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000991163	SCV001142349	pathogenic	Atelosteogenesis type II	2020-01-06	no assertion criteria provided	curation	NG_007147.2(NM_000112.3):c.-26+2T>C in the SLC26A2 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. Makitie O. et al. reported that one patient was homozygous for the Finnish major SLC26A2 mutation IVS1+2T>C, four were compound heterozygotes with this mutation and Arg279Trp and all of them were affected with multiple epiphyseal dysplasia (PMID: 24598000). The SLC26A2 c.-26+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4.
Natera, Inc.	RCV001030744	SCV001452788	pathogenic	Achondrogenesis, type IB	2020-09-16	no assertion criteria provided	clinical testing