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NM_000448.3(RAG1):c.1856C>T (p.Pro619Leu) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 15, 2024
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:
RCV002966260.4

Allele description [Variation Report for NM_000448.3(RAG1):c.1856C>T (p.Pro619Leu)]

NM_000448.3(RAG1):c.1856C>T (p.Pro619Leu)

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.1856C>T (p.Pro619Leu)
HGVS:
  • NC_000011.10:g.36575160C>T
  • NG_007528.1:g.12148C>T
  • NM_000448.3:c.1856C>TMANE SELECT
  • NM_001377277.1:c.1856C>T
  • NM_001377278.1:c.1856C>T
  • NM_001377279.1:c.1856C>T
  • NM_001377280.1:c.1856C>T
  • NP_000439.1:p.Pro619Leu
  • NP_000439.2:p.Pro619Leu
  • NP_001364206.1:p.Pro619Leu
  • NP_001364207.1:p.Pro619Leu
  • NP_001364208.1:p.Pro619Leu
  • NP_001364209.1:p.Pro619Leu
  • LRG_98t1:c.1856C>T
  • LRG_98:g.12148C>T
  • LRG_98p1:p.Pro619Leu
  • NC_000011.9:g.36596710C>T
  • NM_000448.2:c.1856C>T
Protein change:
P619L
Links:
dbSNP: rs755059628
NCBI 1000 Genomes Browser:
rs755059628
Molecular consequence:
  • NM_000448.3:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Combined immunodeficiency with skin 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; SCID, AR, T-cell negative, B-cell negative, NK cell-positive; Severe combined immunodeficiency due to complete RAG1/2 deficiency
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
SCV003277728Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 15, 2024) 		germlineclinical testing

PubMed (2)
[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

Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma.

Chitty-Lopez M, Westermann-Clark E, Dawson I, Ujhazi B, Csomos K, Dobbs K, Le K, Yamazaki Y, Sadighi Akha AA, Chellapandian D, Oshrine B, Notarangelo LD, Sunkersett G, Leiding JW, Walter JE.

Front Immunol. 2020;11:1954. doi: 10.3389/fimmu.2020.01954.

PubMed [citation]
PMID:
33117328
PMCID:
PMC7552884

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, SCV003277728.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 619 of the RAG1 protein (p.Pro619Leu). This variant is present in population databases (rs755059628, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 33117328). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2066890). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. 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.

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

Last Updated: May 16, 2025