Submissions for variant NM_000303.3(PMM2):c.66+1G>T

gnomAD frequency: 0.00001  dbSNP: rs937726878

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780612	SCV000918028	likely pathogenic	PMM2-congenital disorder of glycosylation	2020-09-17	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.66+1G>T 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 1.4e-05 in 219708 control chromosomes (gnomAD). c.66+1G>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (Le Bizec_2005, Leticee_2010, Monin_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000780612	SCV000992590	likely pathogenic	PMM2-congenital disorder of glycosylation	2019-07-03	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000780612	SCV001200999	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 15844218, 20638314). 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: 632948). 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	RCV000780612	SCV002813930	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-03-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000780612	SCV004205314	pathogenic	PMM2-congenital disorder of glycosylation	2022-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV004788188	SCV005401097	likely pathogenic	not provided	2024-05-16	criteria provided, single submitter	clinical testing	Observed with the p.(P20S) variant on the same allele (in cis) as well as another pathogenic variant on the opposite allele (in trans) in patients with features of a congenital disorder of glycosylation in published literature (PMID: 15844218, 20638314, 25497157); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34277356, 25497157, 20638314, 15844218)