NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter) AND Severe combined immunodeficiency due to DCLRE1C deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 8, 2024
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:: RCV002034546.7

Allele description [Variation Report for NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter)]

NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter)

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.571C>T (p.Arg191Ter)

Other names:

NM_001033855.3(DCLRE1C):c.571C>T; p.Arg191Ter

HGVS:

NC_000010.11:g.14934487G>A
NG_007276.1:g.24609C>T
NM_001033855.3:c.571C>TMANE SELECT
NM_001033857.3:c.211C>T
NM_001033858.3:c.211C>T
NM_001289076.2:c.226C>T
NM_001289077.2:c.211C>T
NM_001289078.2:c.226C>T
NM_001289079.2:c.211C>T
NM_001350965.2:c.571C>T
NM_001350966.2:c.226C>T
NM_001350967.2:c.211C>T
NM_022487.4:c.226C>T
NP_001029027.1:p.Arg191Ter
NP_001029029.1:p.Arg71Ter
NP_001029030.1:p.Arg71Ter
NP_001276005.1:p.Arg76Ter
NP_001276006.1:p.Arg71Ter
NP_001276007.1:p.Arg76Ter
NP_001276008.1:p.Arg71Ter
NP_001337894.1:p.Arg191Ter
NP_001337895.1:p.Arg76Ter
NP_001337896.1:p.Arg71Ter
NP_071932.2:p.Arg76Ter
LRG_54:g.24609C>T
NC_000010.10:g.14976486G>A
NR_110297.2:n.869C>T
NR_146960.1:n.993C>T
NR_146961.2:n.686C>T
NR_146962.1:n.993C>T

Protein change:

R191*

Links:

dbSNP: rs752655158

NCBI 1000 Genomes Browser:

rs752655158

Molecular consequence:

NR_110297.2:n.869C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146960.1:n.993C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146961.2:n.686C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146962.1:n.993C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001033855.3:c.571C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001033857.3:c.211C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001033858.3:c.211C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001289076.2:c.226C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001289077.2:c.211C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001289078.2:c.226C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001289079.2:c.211C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001350965.2:c.571C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001350966.2:c.226C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001350967.2:c.211C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_022487.4:c.226C>T - nonsense - [Sequence Ontology: SO:0001587]

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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PREDICTED: Homo sapiens family with sequence similarity 120 member A (FAM120A), ...
PREDICTED: Homo sapiens family with sequence similarity 120 member A (FAM120A), transcript variant X3, mRNA
gi|2462623723|ref|XM_054362503.1|

Nucleotide
PREDICTED: Homo sapiens family with sequence similarity 120 member A (FAM120A), ...
PREDICTED: Homo sapiens family with sequence similarity 120 member A (FAM120A), transcript variant X4, mRNA
gi|2462623725|ref|XM_054362504.1|

Nucleotide
GYF domain-containing protein gyf-1 [Caenorhabditis elegans]
GYF domain-containing protein gyf-1 [Caenorhabditis elegans]
gi|453231778|ref|NP_495360.2|

Protein
G protein-coupled receptor [Caenorhabditis elegans]
G protein-coupled receptor [Caenorhabditis elegans]
gi|71982717|ref|NP_504364.2|

Protein
Caenorhabditis elegans Uncharacterized protein (C18H9.1), partial mRNA
Caenorhabditis elegans Uncharacterized protein (C18H9.1), partial mRNA
gi|1734321718|ref|NM_062962.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002247242	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21664875, 26123418, 32888943, 25917813, 28492532
SCV004810427	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications DCLRE1C V1.0.0)	Pathogenic (Mar 8, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002247242

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 8, 2023)

germline

clinical testing

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

SCV004810427

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications DCLRE1C V1.0.0)

Pathogenic
(Mar 8, 2024)

germline

curation

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

Citation Link

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, curation

Citations

PubMed

Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency.

Felgentreff K, Perez-Becker R, Speckmann C, Schwarz K, Kalwak K, Markelj G, Avcin T, Qasim W, Davies EG, Niehues T, Ehl S.

Clin Immunol. 2011 Oct;141(1):73-82. doi: 10.1016/j.clim.2011.05.007. Epub 2011 May 30. Review.

PubMed [citation]

PMID:: 21664875

Hypomorphic interleukin-7 receptor α-chain mutations and T-cell deficiency: a delay in diagnosis.

Leiding JW, Sriaroon P, Ly JM, Petrovic A, Howard DL, Shamblott M, Kuehn HS, Fleisher TA.

Ann Allergy Asthma Immunol. 2015 Jul;115(1):1-3. doi: 10.1016/j.anai.2015.04.024. No abstract available.

PubMed [citation]

PMID:: 26123418

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002247242.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg191*) in the DCLRE1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418). This variant is present in population databases (rs752655158, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with DCLRE1C-related conditions (PMID: 25917813, 32888943). ClinVar contains an entry for this variant (Variation ID: 1322192). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DCLRE1C function (PMID: 25917813). For these reasons, this variant has been classified as Pathogenic.

#	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 ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV004810427.1

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

Description

The c.571C>T (p.Arg191Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). The filtering allele frequency (the upper threshold of the 95% CI of 2/86258 alleles) of the c.571C>T variant in DCLRE1C is 0.000003850 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.87) and DNA repair (36h after IR): Mean (SD): 0 (12.11). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID: 25917813). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency, based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_Supporting, and PS3_Moderate (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: Sep 29, 2024

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