Submissions for variant NM_002633.3(PGM1):c.247-5696A>T

gnomAD frequency: 0.00069  dbSNP: rs200881174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001400107	SCV001601909	likely benign	PGM1-congenital disorder of glycosylation	2019-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001581119	SCV001819299	uncertain significance	not provided	2019-09-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Observed along with a variant in the MPI gene in an individual with fetal alcohol syndrome (FAS), attention deficit hyperactivity disorder, learning disorder and adenoidhypertrophy in a study assessing possible genetic predisposition to FAS (de la Morena-Barrio ME et al., 2018); This variant is associated with the following publications: (PMID: 28820871)
Genetic Services Laboratory, University of Chicago	RCV001820098	SCV002068366	uncertain significance	not specified	2020-01-31	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PGM1 gene demonstrated a sequence change, c.269A>T, in exon 1 that results in an amino acid change, p.Glu90Val. This sequence change does not appear to have been previously described in patients with PGM1-related disorders and has been described in the gnomAD database with a population frequency of 0.11% in non-Finnish European subpopulation (dbSNP rs200881174). The p.Glu90Val change affects a poorly conserved amino acid residue located in a domain of the PGM1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu90Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu90Val change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001820098	SCV004813934	uncertain significance	not specified	2024-02-14	criteria provided, single submitter	clinical testing	Variant summary: PGM1 c.247-5696A>T is located at a position not widely known to affect splicing. Two of two in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00059 in 240530 control chromosomes (gnomAD) c.247-5696A>T (which is also reported as c.269A>T, p.Glu90Val in pgm1tv2 in NM_001172818) has been reported in the literature in at-least one individual affected with Fetal alcohol syndrome with a non-informative genotype (example: de la Morena-Barrio_2017). This report does not provide unequivocal conclusions about association of the variant with PGM1-Congenital Disorder Of Glycosylation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28820871). ClinVar contains an entry for this variant (Variation ID: 1083445). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001581119	SCV005435758	uncertain significance	not provided	2024-10-01	criteria provided, single submitter	clinical testing