NM_024782.3(NHEJ1):c.743G>C (p.Gly248Ala) AND Cernunnos-XLF deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 27, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001880556.6

Allele description [Variation Report for NM_024782.3(NHEJ1):c.743G>C (p.Gly248Ala)]

NM_024782.3(NHEJ1):c.743G>C (p.Gly248Ala)

Genes:

LOC126806516:BRD4-independent group 4 enhancer GRCh37_chr2:219941606-219942805 [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.743G>C (p.Gly248Ala)

HGVS:

NC_000002.12:g.219077328C>G
NG_007880.1:g.88538G>C
NM_001377498.1:c.743G>C
NM_001377499.1:c.758G>C
NM_024782.2:c.743G>C
NM_024782.3:c.743G>CMANE SELECT
NP_001364427.1:p.Gly248Ala
NP_001364428.1:p.Gly253Ala
NP_079058.1:p.Gly248Ala
LRG_90t1:c.743G>C
LRG_90:g.88538G>C
NC_000002.11:g.219942050C>G
NR_165304.1:n.921G>C

Protein change:

G248A

Links:

dbSNP: rs199723096

NCBI 1000 Genomes Browser:

rs199723096

Molecular consequence:

NM_001377498.1:c.743G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001377499.1:c.758G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024782.3:c.743G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_165304.1:n.921G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002120312	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002120312

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 27, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002120312.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NHEJ1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 248 of the NHEJ1 protein (p.Gly248Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine.

#	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: Sep 29, 2024

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