rs372079206
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_013339.4(ALG6):c.680G>A(p.Gly227Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_013339.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG6 | NM_013339.4 | c.680G>A | p.Gly227Glu | missense_variant, splice_region_variant | 8/15 | ENST00000263440.6 | NP_037471.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALG6 | ENST00000263440.6 | c.680G>A | p.Gly227Glu | missense_variant, splice_region_variant | 8/15 | 5 | NM_013339.4 | ENSP00000263440.5 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249578Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135094
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1460870Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 726686
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
ALG6-congenital disorder of glycosylation 1C Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 28, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 28, 2023 | 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2024 | 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, 36756224) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at