Submissions for variant NM_024105.4(ALG12):c.931C>T (p.Arg311Cys)

gnomAD frequency: 0.00003  dbSNP: rs746215829

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432212	SCV000512017	uncertain significance	not provided	2019-07-13	criteria provided, single submitter	clinical testing	Reported previously, in the compound heterozygous state with another missense variant, in a patient with congenital disorder of glycosylation type Ig (CDG-Ig) (Eklund et al., 2005); Complementation studies demonstrated that wild-type hALG12 was able to correct the biochemical phenotype in fibroblast cells from the affected individual; however functional analysis specifically showing pathogenicity of the R311C variant was not performed and additional studies are needed to validate the functional effect of this specific variant in vivo (Eklund et al., 2005); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15639192)
Mayo Clinic Laboratories, Mayo Clinic	RCV000660616	SCV000782734	uncertain significance	ALG12-congenital disorder of glycosylation	2017-09-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000660616	SCV000896984	uncertain significance	ALG12-congenital disorder of glycosylation	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000660616	SCV003444606	uncertain significance	ALG12-congenital disorder of glycosylation	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 311 of the ALG12 protein (p.Arg311Cys). This variant is present in population databases (rs746215829, gnomAD 0.005%). This missense change has been observed in individual(s) with ALG12-congenital disorder of glycosylation (CDG-Ig) (PMID: 15639192). ClinVar contains an entry for this variant (Variation ID: 377465). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALG12 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055960	SCV005727141	uncertain significance	not specified	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: ALG12 c.931C>T (p.Arg311Cys) 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 1.2e-05 in 251328 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.931C>T has been reported in the literature in an individual affected with ALG12-Congenital Disorder Of Glycosylation (Eklund_2005). 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 publication has been ascertained in the context of this evaluation (PMID: 15639192). ClinVar contains an entry for this variant (Variation ID: 377465). Based on the evidence outlined above, the variant was classified as uncertain significance.