Submissions for variant NM_019109.5(ALG1):c.1342C>T (p.Arg448Ter)

dbSNP: rs1047747

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000430761	SCV000522564	likely pathogenic	not provided	2024-04-23	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 17 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808344	SCV000948451	likely pathogenic	ALG1-congenital disorder of glycosylation	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg448*) in the ALG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the ALG1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital disorder of glycosylation (external communication, internal data). 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: 382581). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.