ClinVar Miner

Submissions for variant NM_024105.4(ALG12):c.671C>T (p.Thr224Met) (rs755892540)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534538 SCV000649500 uncertain significance ALG12-congenital disorder of glycosylation 2019-05-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 224 of the ALG12 protein (p.Thr224Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs755892540, ExAC 0.01%). This variant has not been reported in the literature in individuals with ALG12-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably 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.
Integrated Genetics/Laboratory Corporation of America RCV001260403 SCV001437379 uncertain significance not specified 2020-09-30 criteria provided, single submitter clinical testing Variant summary: ALG12 c.671C>T (p.Thr224Met) 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 2e-05 in 251392 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.671C>T has been reported in the literature in two compound heterozygous brothers who were affected with a mild form of ALG12-Congenital Disorder of Glycosylation (Tahata_2019); both of patients carried the variant c.1001delA (p.N334TfsX15) in trans. The siblings had a type I pattern (characteristic for the disease) on carbohydrate-deficient transferrin analysis, however no in vitro functional studies were performed to evaluate the impact of the variant on protein function, therefore these results do not allow convincing conclusions about the variant effect. Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x) and VUS (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM RCV000534538 SCV001259210 pathogenic ALG12-congenital disorder of glycosylation 2020-05-21 no assertion criteria provided literature only

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