Submissions for variant NM_013339.4(ALG6):c.998C>T (p.Ala333Val)

gnomAD frequency: 0.00003  dbSNP: rs121908443

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000005832	SCV000792595	pathogenic	ALG6-congenital disorder of glycosylation 1C	2017-07-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000005832	SCV000894082	pathogenic	ALG6-congenital disorder of glycosylation 1C	2021-12-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000005832	SCV000915431	pathogenic	ALG6-congenital disorder of glycosylation 1C	2018-08-09	criteria provided, single submitter	clinical testing	The ALG6 c.998C>T (p.Ala333Val) missense variant is reported to be the most common cause of congenital disorders of glycosylation (CDG) (Drijvers et al. 2010; Ichikawa et al. 2013). Across a selection of the available literature, the p.Ala333Val variant has been reported in a total of eight individuals with CDG, including in four homozygotes, comprised of two sibling pairs who are cousins, and in four unrelated compound heterozygotes. This variant was also identified in a heterozygous state in five unaffected parents of the probands (Imbach et al. 1999; Westphal et al. 2000; Drijvers et al. 2010; Ichikawa et al. 2013; Dercksen et al. 2013). The p.Ala333Val variant was absent from controls but is reported at a frequency of 0.000075 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in yeast with a hypoglycosylation phenotype showed that the p.Ala333Val variant was able to only partially restore glycosylation, whereas glycosylation was fully restored with the wild type protein (Imbach et al. 1999; Westphal et al. 2000). Based on the collective evidence, the p.Ala333Val variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000005832	SCV001213979	pathogenic	ALG6-congenital disorder of glycosylation 1C	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 333 of the ALG6 protein (p.Ala333Val). This variant is present in population databases (rs121908443, gnomAD 0.006%). This missense change has been observed in individual(s) with ALG6-congenital disorder of glycosylation (CDG-Ic) (PMID: 10359825, 10914684, 11106564, 20447155, 23430515, 27287710). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5497). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALG6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ALG6 function (PMID: 10359825, 10914684, 11106564). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001547693	SCV001767459	pathogenic	not provided	2022-02-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the A333V variant severely impairs ALG6 protein function and leads to incomplete CPY glycosylation (Imbach et al., 2000; Westphal et al., 2003); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23430515, 27287710, 10852543, 12855228, 11106564, 20447155, 10359825, 10914684, 14517965, 23044053, 15771971, 31589614, 33413482, 31991610)
PreventionGenetics, part of Exact Sciences	RCV003407284	SCV004114863	pathogenic	ALG6-related condition	2023-04-21	criteria provided, single submitter	clinical testing	The ALG6 c.998C>T variant is predicted to result in the amino acid substitution p.Ala333Val. This variant has been reported to be causative for congenital disorder of glycosylation 1c when present in the homozygous or compound heterozygous state (Imbach et al. 1999. PubMed ID: 10359825; Westphal et al. 2000. PubMed ID: 11106564). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-63885051-C-T). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000005832	SCV004197188	pathogenic	ALG6-congenital disorder of glycosylation 1C	2023-07-25	criteria provided, single submitter	clinical testing
OMIM	RCV000005832	SCV000026014	pathogenic	ALG6-congenital disorder of glycosylation 1C	1999-06-08	no assertion criteria provided	literature only
Natera, Inc.	RCV000005832	SCV001456284	pathogenic	ALG6-congenital disorder of glycosylation 1C	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001547693	SCV001809161	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001547693	SCV001957079	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001547693	SCV001964941	likely pathogenic	not provided		no assertion criteria provided	clinical testing