Submissions for variant NM_018297.4(NGLY1):c.1268T>A (p.Leu423Gln)

gnomAD frequency: 0.00006  dbSNP: rs369598638

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000692485	SCV000820310	uncertain significance	Congenital disorder of deglycosylation	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 423 of the NGLY1 protein (p.Leu423Gln). This variant is present in population databases (rs369598638, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 571357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NGLY1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002532215	SCV003551664	uncertain significance	Inborn genetic diseases	2021-07-09	criteria provided, single submitter	clinical testing	The c.1268T>A (p.L423Q) alteration is located in exon 9 (coding exon 9) of the NGLY1 gene. This alteration results from a T to A substitution at nucleotide position 1268, causing the leucine (L) at amino acid position 423 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003424286	SCV004118052	uncertain significance	NGLY1-related condition	2022-12-07	criteria provided, single submitter	clinical testing	The NGLY1 c.1268T>A variant is predicted to result in the amino acid substitution p.Leu423Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-25773967-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003437398	SCV004149320	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	NGLY1: BP4