Submissions for variant NM_018297.4(NGLY1):c.1891del (p.Gln631fs)

dbSNP: rs587776982

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255027	SCV000322043	pathogenic	not provided	2022-11-25	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26252162, 24651605, 27388694, 29550355, 25900930, 30740912, 31957011, 32395402, 32422350, 22581936)
Eurofins Ntd Llc (ga)	RCV000255027	SCV000344216	pathogenic	not provided	2016-08-23	criteria provided, single submitter	clinical testing
Invitae	RCV000043662	SCV000654085	pathogenic	Congenital disorder of deglycosylation	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln631Serfs*7) in the NGLY1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the NGLY1 protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of NGLY1 deficiency (PMID: 24651605, 25900930, 30740912). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1837del (p.Gln613fs). ClinVar contains an entry for this variant (Variation ID: 50961). Studies have shown that this premature translational stop signal alters NGLY1 gene expression (PMID: 22581936, 25900930). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003147331	SCV002018331	pathogenic	Congenital disorder of deglycosylation 1	2019-10-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043662	SCV002511839	pathogenic	Congenital disorder of deglycosylation	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: NGLY1 c.1891delC (p.Gln631SerfsX7) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At-least one study reports a lack of protein expression in leukocytes derived from a compound heterozygous individual harboring this variant and another truncation in the NGLY1 gene (example, Need_2012). The variant allele was found at a frequency of 8e-06 in 251260 control chromosomes. c.1891delC has been reported in the literature as a compound heterozygous genotype in individuals affected with Congenital Disorder Of Deglycosylation (example, Need_2012 cited in He_2015, Rios-Flores_2020, Budhiraja_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36102038, 25900930, 22581936, 32422350). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000043662	SCV000071684	pathogenic	Congenital disorder of deglycosylation	2012-06-01	no assertion criteria provided	literature only