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

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Feb 23, 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:: RCV002477142.8

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

Help

Summary from all submissions

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

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

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

Last Updated: Jun 17, 2024

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