rs121908159

Variant names:

• chr10-14953908-G-C
• rs121908159
• NM_001033855.3:c.103C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_Moderate PP1 PM2_Supporting PS3_Moderate PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp).The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID:25917813).This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320).At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID:24481607).In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA117007/MONDO:0011225/116

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.76
• Publications: 6 publications found

Genes affected

DCLRE1C (HGNC:17642): (DNA cross-link repair 1C) This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair. The encoded protein has single-strand-specific 5'-3' exonuclease activity; it also exhibits endonuclease activity on 5' and 3' overhangs and hairpins. The protein also functions in the regulation of the cell cycle in response to DNA damage. Mutations in this gene can cause Athabascan-type severe combined immunodeficiency (SCIDA) and Omenn syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

DCLRE1C Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet
• severe combined immunodeficiency due to DCLRE1C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3	c.103C>G	p.His35Asp	missense_variant	Exon 1 of 14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.103C>G	p.His35Asp	missense_variant	Exon 1 of 14	1	NM_001033855.3	ENSP00000367527.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250490 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:3

Dec 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 16, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DCLRE1C c.103C>G (p.His35Asp) missense variant has been reported in a single study in which it was identified in a compound heterozygous state in two related individuals (Ege at al. 2005). One proband was clinically diagnosed with Omenn syndrome with symptoms including sepsis, failure to thrive, generalized lymphedema, hepatomegaly, splenomegaly, and erythrodermatitis. The brother was clinically diagnosed with thrombocytopenia and autoimmune hemolytic anemia with a possible diagnosis of Evans syndrome (Ege et al. 2005). Control data are unavailable for the p.His35Asp variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. The p.His35Asp variant causes significantly reduced recombination activity and DNA repair as well as loss of endonuclease activity (Pannicke et al. 2004; Pannicke et al. 2010; Felgentreff et al. 2015). The mean activity level in comparison to the wild type, endogenous control activity for the c.103C>G variant is 0% for mean recombination and 27.29% for mean DNA repair (Felgentreff et al. 2015). Based on the available evidence, the c.103C>G (p.His35Asp) variant is classified as likely pathogenic for Omenn syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Severe combined immunodeficiency due to DCLRE1C deficiency Pathogenic:2

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 4674). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 15731174, 25917813). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 15731174, 24144642). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121908159, gnomAD 0.0009%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 35 of the DCLRE1C protein (p.His35Asp). -

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp). The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID: 25917813). This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320). At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID: 24481607). In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting. -

Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis Pathogenic:1

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		8.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.91		Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);
MVP		1.0
MPC		0.34
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		0.057	Neutral
Varity_R		0.99
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908159; hg19: chr10-14995907;