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NM_000448.3(RAG1):c.2918G>C (p.Arg973Pro) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 29, 2022
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:
RCV001070572.7

Allele description

NM_000448.3(RAG1):c.2918G>C (p.Arg973Pro)

Gene:
RAG1:recombination activating 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p12
Genomic location:
Preferred name:
NM_000448.3(RAG1):c.2918G>C (p.Arg973Pro)
HGVS:
  • NC_000011.10:g.36576222G>C
  • NG_007528.1:g.13210G>C
  • NM_000448.3:c.2918G>CMANE SELECT
  • NM_001377277.1:c.2918G>C
  • NM_001377278.1:c.2918G>C
  • NM_001377279.1:c.2918G>C
  • NM_001377280.1:c.2918G>C
  • NP_000439.2:p.Arg973Pro
  • NP_001364206.1:p.Arg973Pro
  • NP_001364207.1:p.Arg973Pro
  • NP_001364208.1:p.Arg973Pro
  • NP_001364209.1:p.Arg973Pro
  • LRG_98t1:c.2918G>C
  • LRG_98:g.13210G>C
  • NC_000011.9:g.36597772G>C
  • NM_000448.2:c.2918G>C
Protein change:
R973P
Links:
dbSNP: rs1384545687
NCBI 1000 Genomes Browser:
rs1384545687
Molecular consequence:
  • NM_000448.3:c.2918G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2918G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2918G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2918G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2918G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Combined immunodeficiency with skin granulomas
Synonyms:
Combined cellular and humoral immune defects with granulomas
Identifiers:
MONDO: MONDO:0009306; MedGen: C2673536; OMIM: 233650
Name:
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
Synonyms:
SCID, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-POSITIVE; Severe immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive; SCID, AR, T-cell negative, B-cell negative, NK cell-positive; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011086; MedGen: C1832322; Orphanet: 331206; OMIM: 601457

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001235828Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Nov 29, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome.

Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist FL, Fischer A, de Villartay JP.

Blood. 2001 May 1;97(9):2772-6.

PubMed [citation]
PMID:
11313270

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency.

Luk ADW, Lee PP, Mao H, Chan KW, Chen XY, Chen TX, He JX, Kechout N, Suri D, Tao YB, Xu YB, Jiang LP, Liew WK, Jirapongsananuruk O, Daengsuwan T, Gupta A, Singh S, Rawat A, Abdul Latiff AH, Lee ACW, Shek LP, Nguyen TVA, et al.

Front Immunol. 2017;8:808. doi: 10.3389/fimmu.2017.00808.

PubMed [citation]
PMID:
28747913
PMCID:
PMC5506088
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001235828.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg973 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313270, 28747913, 30307608). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt RAG1 protein function. ClinVar contains an entry for this variant (Variation ID: 863578). This variant has not been reported in the literature in individuals affected with RAG1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 973 of the RAG1 protein (p.Arg973Pro).

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

Last Updated: Mar 5, 2024