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NM_024782.3(NHEJ1):c.464C>T (p.Thr155Met) AND Cernunnos-XLF deficiency

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Dec 15, 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:
RCV001322201.5

Allele description

NM_024782.3(NHEJ1):c.464C>T (p.Thr155Met)

Gene:
NHEJ1:non-homologous end joining factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_024782.3(NHEJ1):c.464C>T (p.Thr155Met)
HGVS:
  • NC_000002.12:g.219147722G>A
  • NG_007880.1:g.18144C>T
  • NM_001377498.1:c.464C>T
  • NM_001377499.1:c.464C>T
  • NM_024782.3:c.464C>TMANE SELECT
  • NP_001364427.1:p.Thr155Met
  • NP_001364428.1:p.Thr155Met
  • NP_079058.1:p.Thr155Met
  • LRG_90:g.18144C>T
  • NC_000002.11:g.220012444G>A
  • NR_165304.1:n.560C>T
Protein change:
T155M
Links:
dbSNP: rs756563868
NCBI 1000 Genomes Browser:
rs756563868
Molecular consequence:
  • NM_001377498.1:c.464C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377499.1:c.464C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024782.3:c.464C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_165304.1:n.560C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Cernunnos-XLF deficiency (IMD124)
Synonyms:
SCID, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE, WITH MICROCEPHALY, GROWTH RETARDATION, AND SENSITIVITY TO IONIZING RADIATION; NHEJ1 SYNDROME; Severe combined immunodeficiency with sensitivity to ionizing radiation due to NHEJ1 deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012650; MedGen: C1969799; Orphanet: 169079; OMIM: 611291

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001513062Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Dec 15, 2023)
germlineclinical testing

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

SCV002814854Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(May 12, 2022)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

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

Details of each submission

From Invitae, SCV001513062.4

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 155 of the NHEJ1 protein (p.Thr155Met). This variant is present in population databases (rs756563868, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NHEJ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022313). 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 NHEJ1 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.

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

From Fulgent Genetics, Fulgent Genetics, SCV002814854.1

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

Last Updated: Sep 1, 2024