NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg) AND Severe combined immunodeficiency due to DCLRE1C deficiency

Germline classification:: Benign (4 submissions)
Last evaluated:: Nov 14, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000560374.19

Allele description [Variation Report for NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg)]

NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg)

Gene:

DCLRE1C:DNA cross-link repair 1C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10p13

Genomic location:

Preferred name:

NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg)

Other names:

NM_001033855.3(DCLRE1C):c.457G>A

HGVS:

NC_000010.11:g.14935470C>T
NG_007276.1:g.23626G>A
NM_001033855.3:c.457G>AMANE SELECT
NM_001033857.3:c.97G>A
NM_001033858.3:c.97G>A
NM_001289076.2:c.112G>A
NM_001289077.2:c.97G>A
NM_001289078.2:c.112G>A
NM_001289079.2:c.97G>A
NM_001350965.2:c.457G>A
NM_001350966.2:c.112G>A
NM_001350967.2:c.97G>A
NM_022487.4:c.112G>A
NP_001029027.1:p.Gly153Arg
NP_001029029.1:p.Gly33Arg
NP_001029030.1:p.Gly33Arg
NP_001276005.1:p.Gly38Arg
NP_001276006.1:p.Gly33Arg
NP_001276007.1:p.Gly38Arg
NP_001276008.1:p.Gly33Arg
NP_001337894.1:p.Gly153Arg
NP_001337895.1:p.Gly38Arg
NP_001337896.1:p.Gly33Arg
NP_071932.2:p.Gly38Arg
LRG_54t1:c.457G>A
LRG_54:g.23626G>A
NC_000010.10:g.14977469C>T
NM_001033855.1:c.457G>A
NM_001033855.2:c.457G>A
NM_001033857.1:c.97G>A
NM_001033858.1:c.97G>A
NR_110297.2:n.755G>A
NR_146960.1:n.879G>A
NR_146961.2:n.572G>A
NR_146962.1:n.879G>A

Protein change:

G153R

Links:

dbSNP: rs41297018

NCBI 1000 Genomes Browser:

rs41297018

Molecular consequence:

NM_001033855.3:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001033857.3:c.97G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001033858.3:c.97G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289076.2:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289077.2:c.97G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289078.2:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289079.2:c.97G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350965.2:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350966.2:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350967.2:c.97G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_022487.4:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_110297.2:n.755G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146960.1:n.879G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146961.2:n.572G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146962.1:n.879G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Severe combined immunodeficiency due to DCLRE1C deficiency (RS-SCID)
Synonyms:: Severe combined immunodeficiency with sensitivity to ionizing radiation; SCID, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE, WITH SENSITIVITY TO IONIZING RADIATION
Identifiers:: MONDO: MONDO:0011225; MedGen: C1865370; Orphanet: 275; OMIM: 602450

Recent activity

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BWG_0635 AND (alive[prop]) (0)
Gene
Ligase I, DNA, ATP-dependent [Rattus norvegicus]
Ligase I, DNA, ATP-dependent [Rattus norvegicus]
gi|62471446|gb|AAH93604.1|

Protein
Gm34244 predicted gene, 34244 [Mus musculus]
Gm34244 predicted gene, 34244 [Mus musculus]
Gene ID:102637437

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000645228	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001138004	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001622933	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jul 9, 2020)	inherited	clinical testing	Citation Link,
SCV004102786	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications DCLRE1C V1.0.0)	Benign (Nov 14, 2023)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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, curation
not provided	inherited	unknown	1	not provided	not provided	1	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, SCV000645228.6

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001138004.1

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

#	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 New York Genome Center - CSER-NYCKidSeq, SCV001622933.1

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

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

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004102786.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg). The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting). Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

#	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: Nov 3, 2024

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