ClinVar Miner

Submissions for variant NM_000112.3(SLC26A2):c.-26+2T>C (rs386833492)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000597319 SCV000789503 pathogenic Multiple epiphyseal dysplasia 4 2017-02-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 2; Multiple epiphyseal dysplasia 4; Diastrophic dysplasia 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000004312 SCV000086695 pathologic Diastrophic dysplasia 2013-07-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779466 SCV000916094 pathogenic SLC26A2-Related Disorders 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.
Integrated Genetics/Laboratory Corporation of America RCV000780711 SCV000918218 pathogenic 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.
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.
OMIM RCV000004312 SCV000024483 pathogenic Diastrophic dysplasia 2008-12-01 no assertion criteria provided literature only

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