Submissions for variant NM_013339.4(ALG6):c.53G>A (p.Arg18Gln)

gnomAD frequency: 0.00002  dbSNP: rs1287725303

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668050	SCV000792593	uncertain significance	ALG6-congenital disorder of glycosylation 1C	2017-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV000668050	SCV002287539	uncertain significance	ALG6-congenital disorder of glycosylation 1C	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the ALG6 protein (p.Arg18Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with ALG6-congenital disorder of glycosylation (PMID: 19862844, 27287710). ClinVar contains an entry for this variant (Variation ID: 552732). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV002225711	SCV002504137	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing	Reported in association with CDG-Ic in published literature (Haeuptle et al., 2009; Vleugels et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15657601, 27287710, 19862844, 21315133)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226356	SCV003923046	uncertain significance	not specified	2023-03-10	criteria provided, single submitter	clinical testing	Variant summary: ALG6 c.53G>A (p.Arg18Gln) results in a conservative amino acid change in the encoded protein sequence. Four 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 248926 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.53G>A has been reported in the Euroglycan network in association with CDG (Haeuptle_2009, Morava_2016) and in the literature in one compound heterozygous individual affected with Congenital Disorder Of Glycosylation (Vleugels_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and as likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.