Submissions for variant NM_000303.3(PMM2):c.255+1G>A

gnomAD frequency: 0.00002  dbSNP: rs1060499598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477824	SCV000757676	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-15	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 (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with congenital disorder of glycosylation I (PMID: 11156536, 15844218, 18948042, 23806237, 28373276). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 417920). 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.
Fulgent Genetics, Fulgent Genetics	RCV000477824	SCV000894090	pathogenic	PMM2-congenital disorder of glycosylation	2022-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000477824	SCV000920016	likely pathogenic	PMM2-congenital disorder of glycosylation	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.255+1G>A 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: Five 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 1.2e-05 in 246154 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (1.2e-05 vs 0.0056), allowing no conclusion about variant significance. c.255+1G>A has been reported in the literature in at least one individual affected with Congenital Disorder of Glycosylation Type 1a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000477824	SCV002060128	likely pathogenic	PMM2-congenital disorder of glycosylation	2021-11-03	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.255+1G>A is a canonical splice variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. c.255+1G>A has been observed in cases with relevant disease (PMID: 15844218). Functional assessments of this variant are available in the literature (PMID: 15844218). c.255+1G>A has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, NM_000303.2(PMM2):c.255+1G>A 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	RCV000477824	SCV004205279	pathogenic	PMM2-congenital disorder of glycosylation	2023-06-01	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477824	SCV000536849	pathogenic	PMM2-congenital disorder of glycosylation	2016-02-17	no assertion criteria provided	research