Submissions for variant NM_013339.4(ALG6):c.680G>A (p.Gly227Glu)

gnomAD frequency: 0.00001  dbSNP: rs372079206

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442361	SCV000520888	likely pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Not observed at 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: 12357336, 23430515, 27287710)
Baylor Genetics	RCV000664900	SCV001523917	pathogenic	ALG6-congenital disorder of glycosylation 1C	2020-11-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000664900	SCV001588921	pathogenic	ALG6-congenital disorder of glycosylation 1C	2023-08-10	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs372079206, gnomAD 0.01%). This missense change has been observed in individual(s) with ALG6-related congenital disorder of glycosylation (PMID: 23430515, 27287710). ClinVar contains an entry for this variant (Variation ID: 381535). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 227 of the ALG6 protein (p.Gly227Glu). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon.
Myriad Genetics, Inc.	RCV000664900	SCV002060256	uncertain significance	ALG6-congenital disorder of glycosylation 1C	2021-11-08	criteria provided, single submitter	clinical testing	NM_013339.3(ALG6):c.680G>A(G227E) is a missense variant classified as a variant of uncertain significance in the context of congenital disorder of glycosylation type Ic. G227E has been observed in cases with relevant disease (PMID: 27287710). Functional assessments of this variant are not available in the literature. G227E has been observed in population frequency databases (gnomAD: AFR 0.007%). In summary, there is insufficient evidence to classify NM_013339.3(ALG6):c.680G>A(G227E) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664900	SCV004037645	pathogenic	ALG6-congenital disorder of glycosylation 1C	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: ALG6 c.680G>A (p.Gly227Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 249578 control chromosomes (gnomAD). c.680G>A has been reported in the literature in multiple individuals affected with ALG6-related congenital disorder of glycosylation (examples: Schollen_2002, Dercksen_2012, Morava_2016, Clark_2023). These data indicate that the variant is very likely to be associated with disease. 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: 36756224, 23430515, 27287710, 12357336). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.