ClinVar Miner

Submissions for variant NM_019109.4(ALG1):c.1250_1251insTG (p.Ala418fs) (rs746019074)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478632 SCV000574137 likely pathogenic not provided 2017-03-13 criteria provided, single submitter clinical testing The c.1250_1251insTG variant in the ALG1 gene has been reported previously in association with congenital disorder of glycosylation type 1k (Ng et al., 2016; Fiumara et al., 2016). This variant causes a frameshift starting with codon Alanine 418, changes this amino acid to a Glutamic Acid residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Ala418GlufsX18. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 47 amino acids of the protein are replaced with 17 incorrect amino acids. The c.1250_1251insTG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1250_1251insTG is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000691959 SCV000819760 pathogenic Congenital disorder of glycosylation type 1K 2017-12-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ALG1 gene (p.Ala418Glufs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the ALG1 protein. This variant is present in population databases (rs746019074, ExAC 0.002%). This variant has been reported in several individuals affected with congenital disorders of glycosylation (PMID: 26931382, 26453362). ClinVar contains an entry for this variant (Variation ID: 424339). A different missense variant (p.Arg438Trp) that lies downstream of this variant has been determined to be pathogenic (PMID: 26931382, 20679665). This suggests that deletion of this region of the ALG1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
University of Washington Center for Mendelian Genomics,University of Washington RCV000851248 SCV000993500 likely pathogenic Congenital disorder of glycosylation 2017-05-25 no assertion criteria provided research

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