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

gnomAD frequency: 0.00007  dbSNP: rs139716296

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000410938	SCV000399670	pathogenic	PMM2-congenital disorder of glycosylation	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.
Fulgent Genetics, Fulgent Genetics	RCV000410938	SCV000894091	pathogenic	PMM2-congenital disorder of glycosylation	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410938	SCV000920014	pathogenic	PMM2-congenital disorder of glycosylation	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410938	SCV000956989	pathogenic	PMM2-congenital disorder of glycosylation	2024-10-17	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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs139716296, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with PMM2-related congenital disorder of glycosylation (PMM2-CDG) (PMID: 11156536, 15844218, 18948042, 23806237). This variant is also known as IVS3+2C>T. ClinVar contains an entry for this variant (Variation ID: 321216). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000410938	SCV001425375	pathogenic	PMM2-congenital disorder of glycosylation	2020-05-19	criteria provided, single submitter	clinical testing	This PMM2 variant is predicted to destroy the native canonical splice donor site in exon 2. PMM2 c.255+2T>C has been reported in an individual with congenital disorder of glycosylation. This variant (rs139716296) is rare (<0.1%) in a large population dataset (gnomAD: 19/282690 total alleles; 0.007%; no homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic.
Diagnostic Laboratory, Strasbourg University Hospital	RCV001257699	SCV001434510	pathogenic	Intellectual disability	2020-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001550143	SCV001770430	pathogenic	not provided	2021-12-06	criteria provided, single submitter	clinical testing	Identified in other patients with congenital disorders of glycosylation in published literature (Jones et al., 2013; Matthijs et al., 1999); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25497157, 25525159, 23430838, 28139241, 23806237, 31980526, 31589614, 34277356, 18948042, 12705494, 11156536, 15844218, 10527672)
Revvity Omics, Revvity	RCV000410938	SCV002018870	pathogenic	PMM2-congenital disorder of glycosylation	2021-06-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410938	SCV002060329	pathogenic	PMM2-congenital disorder of glycosylation	2021-10-01	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.255+2T>C is a canonical splice variant classified as pathogenic in the context of congenital disorder of glycosylation type Ia. c.255+2T>C has been observed in cases with relevant disease (PMID: 12705494, 15844218). Functional assessments of this variant are not available in the literature. c.255+2T>C has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, NM_000303.2(PMM2):c.255+2T>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000410938	SCV004205253	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021683	SCV005009707	pathogenic	Inborn genetic diseases	2021-03-25	criteria provided, single submitter	clinical testing	The c.255+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 3 of the PMM2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.255+2T>C alteration was observed in 0.01% (19/282690) of total alleles studied, with a frequency of 0.01% (5/35424) in the Latino subpopulation. This mutation (also known as IVS3+2C>T in the literature) has been detected as compound heterozygous with a second PMM2 mutation in many individuals with congenital disorder of glycosylation 1A (Hou, 2020; Matthijs,1999; Gr&uuml;newald, 2001; Briones, 2002). This nucleotide position is highly conserved in available vertebrate species. This mutation was shown to significantly impact phosphomannomutase activity in fibroblasts and leukocytes compared to wild type (Gr&uuml;newald, 2001). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Natera, Inc.	RCV000410938	SCV001457166	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001550143	SCV001955050	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001550143	SCV001970084	pathogenic	not provided		no assertion criteria provided	clinical testing