Submissions for variant NM_000303.3(PMM2):c.178G>T (p.Val60Leu)

gnomAD frequency: 0.00001  dbSNP: rs759513930

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636240	SCV000757673	pathogenic	PMM2-congenital disorder of glycosylation	2024-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 60 of the PMM2 protein (p.Val60Leu). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs759513930, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical and biochemical features consistent with PMM2-CDG (internal data). 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: 530390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Genomic Medicine Lab, University of California San Francisco	RCV000636240	SCV001573002	likely pathogenic	PMM2-congenital disorder of glycosylation	2019-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001597192	SCV001831995	pathogenic	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Transversion change at the evolutionarily conserved last nucleotide position of exon 2 in a gene for which loss-of-function is a known mechanism of disease. In silico predictors support a potential splicing effect with the adjacent exon out of frame and studies in patient cells support this variant results in abnormal splicing (Gonzlez-Domnguez CA et al., 2021); This variant is associated with the following publications: (PMID: 26633542, 34277356)
3billion, Medical Genetics	RCV000636240	SCV003841277	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 34277356). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMM2 related disorder (ClinVar ID: VCV000530390 / PMID: 26633542). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000636240	SCV003922622	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.178G>T (p.Val60Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example:Gonzalez-Dominguez_2021). The variant allele was found at a frequency of 2.4e-05 in 245166 control chromosomes (gnomAD). c.178G>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation and Developmental brain disorder (example: Gonzalez-Dominguez_2021 and Aldinger_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000636240	SCV004205251	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-02-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000636240	SCV000896574	uncertain significance	PMM2-congenital disorder of glycosylation	2018-10-31	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755996	SCV005360846	pathogenic	PMM2-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The PMM2 c.178G>T variant is predicted to result in the amino acid substitution p.Val60Leu. This variant has been reported in the compound heterozygous state with a second disease-causing PMM2 variant in multiple individuals with congenital disorder of glycosylation type 1a (PMM2-CDG) (González-Domínguez et al. 2021. PubMed ID: 34277356; De Graef et al. 2023. PubMed ID: 37224763; Hall et al. 2024. PubMed ID: 39216211; PreventionGenetics internal data). It has also been reported in the presumed compound heterozygous state (with p.Arg141His) in a cohort of individuals with cerebellar malformations (Table S9, Aldinger et al. 2019. PubMed ID: 31474318). RNA sequencing analysis performed using cultured patient fibroblasts confirmed that the c.178G>T variant disrupted splicing at the adjacent canonical splice donor site, leading to the activation of two intronic cryptic donor sites (González-Domínguez et al. 2021. PubMed ID: 34277356). The inclusion of intronic sequence in the resulting mRNA is expected to lead to a frameshift (p.Val60Cysfs*3) and premature protein termination. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in PMM2 are expected to be pathogenic. This variant is interpreted as pathogenic.