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

Clinical significance:Pathogenic (Last evaluated: Oct 28, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000043663.15

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
  • 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 (CDDG)
Synonyms:
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv
Identifiers:
MONDO: MONDO:0014109; MedGen: C3808991; Orphanet: 404454; OMIM: 615273

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000071685OMIMno assertion criteria providedPathogenic
(Mar 20, 2014)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV000258427Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicinecriteria provided, single submitter
Pathogenic
(Sep 9, 2015)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

SCV000654066Invitaecriteria provided, single submitter
Pathogenic
(Oct 28, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000891725GeneReviewsno assertion criteria providedPathogenic
(Aug 25, 2017)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000894311Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001526742Baylor Geneticscriteria provided, single submitter
Pathogenic
(Jan 22, 2018)
paternalclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineno2not providednot providednot providednot providedresearch
not providedpaternalyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyes11not providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedliterature only, clinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.

Panneman DM, Wortmann SB, Haaxma CA, van Hasselt PM, Wolf NI, Hendriks Y, K├╝sters B, van Emst-de Vries S, van de Westerlo E, Koopman WJH, Wintjes L, van den Brandt F, de Vries M, Lefeber DJ, Smeitink JAM, Rodenburg RJ.

Clin Genet. 2020 Apr;97(4):556-566. doi: 10.1111/cge.13706. Epub 2020 Jan 30.

PubMed [citation]
PMID:
31957011
PMCID:
PMC7078978

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000071685.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

For discussion of the arg401-to-ter (R401X) mutation in the NGLY1 gene that was found in compound heterozygous state in a patient with congenital disorder of deglycosylation (CDDG; 615273) by Need et al. (2012), see 610661.0001.

In 5 patients from 3 families with CDDG, Enns et al. (2014) identified a homozygous c.1201A-T transversion in exon 8 of the NGLY1 gene, resulting in an arg401-to-ter (R401X) substitution. All of the patients were Caucasian and of European descent, suggesting the possibility of a founder mutation. The R401X mutation was found in 2 of 8,598 chromosomes of European ancestry and once among African American chromosomes in the Exome Variant Server database.

The R401X mutation was the most common among the 12 individuals studied by Lam et al. (2017), accounting for 7 alleles.

In 3 unrelated patients with CDDG, Panneman et al. (2020) identified the R401X mutation in the NGLY1 gene: patient 2 was homozygous for the mutation, whereas patient 1 also had a c.849T-G transversion, resulting in a cys283-to-trp (C283W; 610661.0006) substitution, and patient 3 had a c.1067A-G transition, resulting in a glu356-to-gly (E356G; 610661.0007) substitution. The mutations were identified by whole-exome sequencing, and the parents in all families were confirmed to be carriers. Western blot analysis in patient muscle tissue and fibroblasts showed absence of NGLY1 protein expression.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000258427.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (1)
2not provided2not providednot providedresearch PubMed (1)

Description

This study shows that diverse genetic causes underlie CVI.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not provided1not provided
2germlinenonot providednot providednot provided2not providednot providednot provided

From Invitae, SCV000654066.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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. This variant is present in population databases (rs201337954, ExAC 0.03%). This particular variant has been reported in the literature in several homozygous or compound heterozygous individuals with NGLY1 deficiency (PMID: 24651605, 26350515, 27388694). ClinVar contains an entry for this variant (Variation ID: 50962). Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000891725.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics,Fulgent Genetics, SCV000894311.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001526742.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

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]

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 24, 2021

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