NM_018297.4(NGLY1):c.1201A>T (p.Arg401Ter) AND Congenital disorder of deglycosylation 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002477142.9

Allele description [Variation Report for NM_018297.4(NGLY1):c.1201A>T (p.Arg401Ter)]

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

Gene:

NGLY1:N-glycanase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p24.2

Genomic location:

Preferred name:

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

HGVS:

NC_000003.12:g.25733931T>A
NG_034108.1:g.61109A>T
NM_001145293.2:c.1147A>T
NM_001145294.2:c.1075A>T
NM_001145295.2:c.1201A>T
NM_018297.4:c.1201A>TMANE SELECT
NP_001138765.1:p.Arg383Ter
NP_001138766.1:p.Arg359Ter
NP_001138767.1:p.Arg401Ter
NP_060767.2:p.Arg401Ter
NC_000003.11:g.25775422T>A
NM_018297.3:c.1201A>T

Protein change:

R359*; ARG401TER

Links:

OMIM: 610661.0002; dbSNP: rs201337954

NCBI 1000 Genomes Browser:

rs201337954

Molecular consequence:

NM_001145293.2:c.1147A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001145294.2:c.1075A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001145295.2:c.1201A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018297.4:c.1201A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Congenital disorder of deglycosylation 1
Synonyms:: NGLY1-deficiency
Identifiers:: MONDO: MONDO:0800044; MedGen: CN306977; Orphanet: 404454; OMIM: 615273

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000894311	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799093	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003834902	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 15, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841933	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22581936, 25741868
SCV005086562	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32071843, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical application of exome sequencing in undiagnosed genetic conditions.

Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DB.

J Med Genet. 2012 Jun;49(6):353-61. doi: 10.1136/jmedgenet-2012-100819. Epub 2012 May 11.

PubMed [citation]

PMID:: 22581936
PMCID:: PMC3375064

NGLY1 deficiency: Novel patient, review of the literature and diagnostic algorithm.

Lipiński P, Bogdańska A, Różdżyńska-Świątkowska A, Wierzbicka-Rucińska A, Tylki-Szymańska A.

JIMD Rep. 2020 Jan;51(1):82-88. doi: 10.1002/jmd2.12086.

PubMed [citation]

PMID:: 32071843
PMCID:: PMC7012742

See all PubMed Citations (3)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000894311.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003799093.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1, PM3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV003834902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841933.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086562.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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