ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.255+2T>C (rs139716296)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410938 SCV000485687 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2016-06-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000410938 SCV000894091 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410938 SCV000399670 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-04-27 criteria provided, single submitter clinical testing The PMM2 c.255+2T>C variant, also known as IVS3+2T>C, occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.255+2T>C variant has been reported in eight studies in which it is found in at least seven affected individuals, including two siblings, in a compound heterozygous state with another missense variant, and in one individual with unspecified zygosity (Matthijs et al. 1999; Grünewald et al. 2001; Briones et al. 2002; Le Bizec et al. 2005; Pérez-Dueñas et al. 2009; Pérez et al. 2011; Jones et al. 2013; Monin et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. The phosphomannomutase activity in fibroblasts and leukocytes from patients with the variant was significantly reduced compared to normal (Grunewald et al. 2001; Perez-Duenas et al. 2009). Based on the evidence, the c.255+2T>C variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000410938 SCV000920014 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-05-11 criteria provided, single submitter clinical testing Variant summary: PMM2 c.255+2T>C is located in a canonical splice-site 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.5e-05 in 277094 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (6.5e-05 vs 0.0056), allowing no conclusion about variant significance. The variant, c.255+2T>C, has been reported in the literature in multiple individuals from families affected with Congenital Disorder of Glycosylation Type 1a (Grunewald_2001, Jones_2013, Le Bizec_2005, Monin_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Grunewald_2001). The most pronounced variant effect results in 10%-<30% of normal activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000410938 SCV000956989 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-12-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the PMM2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs139716296, ExAC 0.02%). This variant has been observed in combination with another PMM2 variant in individuals affected with PMM2-related congenital disorder of glycosylation (PMM2-CDG) (PMID: 18948042, 23806237, 11156536, 15844218). This variant is also known as IVS3+2C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 321216). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). For these reasons, this variant has been classified as Pathogenic.

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