ClinVar Miner

Submissions for variant NM_000112.3(SLC26A2):c.532C>T (p.Arg178Ter) (rs104893919)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000412934 SCV000227019 pathogenic not provided 2014-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000412934 SCV000491205 pathogenic not provided 2016-09-16 criteria provided, single submitter clinical testing The R178X pathogenic variant is one of the most common pathogenic variants observed in association with SLC26A2-related skeletal dysplasias (Rossi A et al. 2001; Superti-Furga A et al. 1996; Panzer et al. 2008). It has been observed in approximately 0.1% (1/8600) of alleles in individuals of European ancestry in the NHLBI Exome Sequencing Project. The R178X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Integrated Genetics/Laboratory Corporation of America RCV000590163 SCV000695419 pathogenic Osteochondrodysplasia 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The SLC26A2 c.532C>T (p.Arg178X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC26A2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1724delA). One in silico tool predicts a damaging outcome for this variant, which has been confirmed by at least one functional study (Karniski_2004). This variant was found in 13/120994 control chromosomes at a frequency of 0.0001074, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC26A2 variant (0.002958). This variant has been reported in multiple STRO patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000690242 SCV000817923 pathogenic Achondrogenesis, type IB; Atelosteogenesis type 2; Multiple epiphyseal dysplasia 4; Diastrophic dysplasia 2018-08-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg178*) in the SLC26A2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104893919, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another SLC26A2 variant in several individuals affected with SLC26A2-related disease (PMID: 8528239, 15316973, 18925670, 21155763). Loss-of-function variants in SLC26A2 are known to be pathogenic (PMID: 7923357, 8528239, 8571951, 10482955, 11241838, 12525546, 20592910, 21077202). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779467 SCV000916095 pathogenic SLC26A2-Related Disorders 2018-10-19 criteria provided, single submitter clinical testing The SLC26A2 c.532C>T (p.Arg178Ter) variant is a stop-gained variant. Across a selection of literature, the p.Arg178Ter variant has been reported in a compound heterozygous state in at least 13 probands (Superti-Furga 1996; Macías-Gómez et al. 2004; Panzer et al. 2008; Barbosa et al. 2011; Mattos et al. 2014). In at least one family an unaffected father was heterozygous for this variant. The p.Arg178Ter variant was absent from at least 200 controls, but is reported at a frequency of 0.00029 in the Latino population from the Genome Aggregation Database. In Xenopus oocytes, the p.Arg178Ter variant was shown to have significantly reduced (<10%) sulfate transport compared to wildtype, and similar findings were noted in HEK-293 cells (Karniski et al. 2001; Karniski et al. 2004). Based on the collective evidence, the p.Arg178Ter 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.
OMIM RCV000004310 SCV000024478 pathogenic Diastrophic dysplasia 2008-11-15 no assertion criteria provided literature only
OMIM RCV000023568 SCV000044859 pathogenic Achondrogenesis, type IB 2008-11-15 no assertion criteria provided literature only
GeneReviews RCV000004310 SCV000086703 pathologic Diastrophic dysplasia 2013-07-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000004310 SCV000487409 pathogenic Diastrophic dysplasia 2016-02-19 no assertion criteria provided clinical testing
Counsyl RCV000175526 SCV000487410 pathogenic Multiple epiphyseal dysplasia 4 2016-02-19 no assertion criteria provided clinical testing
Counsyl RCV000411745 SCV000487411 pathogenic Atelosteogenesis type 2 2016-02-19 no assertion criteria provided clinical testing
Counsyl RCV000023568 SCV000487412 pathogenic Achondrogenesis, type IB 2016-02-19 no assertion criteria provided clinical testing

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