Submissions for variant NM_002435.3(MPI):c.748G>A (p.Gly250Ser)

gnomAD frequency: 0.00010  dbSNP: rs748090636

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593845	SCV000706884	uncertain significance	not provided	2017-03-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000671942	SCV000796984	uncertain significance	MPI-congenital disorder of glycosylation	2018-01-05	criteria provided, single submitter	clinical testing
3billion	RCV000671942	SCV002572750	uncertain significance	MPI-congenital disorder of glycosylation	2022-09-01	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: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MPI-related disorder (PMID: 10980531). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330818	SCV004038493	uncertain significance	not specified	2023-08-09	criteria provided, single submitter	clinical testing	Variant summary: MPI c.748G>A (p.Gly250Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.748G>A has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation (e.g. Schollen_2000, Lipinski_2021, Bogdanska_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33407696, 33643843, 10980531). Three ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.