Submissions for variant NM_018297.4(NGLY1):c.1201A>T (p.Arg401Ter)

gnomAD frequency: 0.00031  dbSNP: rs201337954

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000043663	SCV000258427	pathogenic	Congenital disorder of deglycosylation	2015-09-09	criteria provided, single submitter	research	This study shows that diverse genetic causes underlie CVI.
GeneDx	RCV000309063	SCV000329581	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Nonsense 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: 26611529, 24651605, 32395402, 22581936, 26350515, 28750948, 27388694, 32071843, 32576142, 32422350, 33057211, 31965062, 31957011, 33673403, 34426522)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043663	SCV000654066	pathogenic	Congenital disorder of deglycosylation	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg401*) in the NGLY1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605). This variant is present in population databases (rs201337954, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with NGLY1 deficiency (PMID: 24651605, 26350515, 27388694). ClinVar contains an entry for this variant (Variation ID: 50962). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002477142	SCV000894311	pathogenic	Congenital disorder of deglycosylation 1	2024-05-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000309063	SCV001334701	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000309063	SCV001447023	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000043663	SCV001526742	pathogenic	Congenital disorder of deglycosylation	2018-01-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with NGLY1 deficiency [PMID 22581936, 26350515, 24651605, 27388694]
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043663	SCV002547508	pathogenic	Congenital disorder of deglycosylation	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: NGLY1 c.1201A>T (p.Arg401X) 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. The variant allele was found at a frequency of 0.00018 in 251186 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NGLY1 causing Congenital Disorder Of Deglycosylation (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.1201A>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Congenital Disorder Of Deglycosylation (example, Enns_2014). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002477142	SCV003799093	likely pathogenic	Congenital disorder of deglycosylation 1	2022-10-10	criteria provided, single submitter	clinical testing	PVS1, PM3
Baylor Genetics	RCV002477142	SCV003834902	pathogenic	Congenital disorder of deglycosylation 1	2021-02-15	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV002477142	SCV003841933	pathogenic	Congenital disorder of deglycosylation 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. Shared with similarly affected family member (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000050962 / PMID: 22581936). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002477142	SCV005086562	pathogenic	Congenital disorder of deglycosylation 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of deglycosylation (MIM#615273). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (52 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with congenital disorders of deglycosylation in both homozygous and compound heterozygous states (ClinVar, DECIPHER, PMID: 32071843). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000043663	SCV000071685	pathogenic	Congenital disorder of deglycosylation	2014-03-20	no assertion criteria provided	literature only
GeneReviews	RCV000043663	SCV000891725	not provided	Congenital disorder of deglycosylation		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000309063	SCV001740562	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000309063	SCV001800049	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000309063	SCV001959855	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000309063	SCV001968799	pathogenic	not provided		no assertion criteria provided	clinical testing