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NM_000448.3(RAG1):c.2009C>T (p.Thr670Met) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 28, 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:
RCV001066664.7

Allele description [Variation Report for NM_000448.3(RAG1):c.2009C>T (p.Thr670Met)]

NM_000448.3(RAG1):c.2009C>T (p.Thr670Met)

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.2009C>T (p.Thr670Met)
HGVS:
  • NC_000011.10:g.36575313C>T
  • NG_007528.1:g.12301C>T
  • NM_000448.3:c.2009C>TMANE SELECT
  • NM_001377277.1:c.2009C>T
  • NM_001377278.1:c.2009C>T
  • NM_001377279.1:c.2009C>T
  • NM_001377280.1:c.2009C>T
  • NP_000439.2:p.Thr670Met
  • NP_001364206.1:p.Thr670Met
  • NP_001364207.1:p.Thr670Met
  • NP_001364208.1:p.Thr670Met
  • NP_001364209.1:p.Thr670Met
  • LRG_98t1:c.2009C>T
  • LRG_98:g.12301C>T
  • NC_000011.9:g.36596863C>T
  • NM_000448.2:c.2009C>T
Protein change:
T670M
Links:
dbSNP: rs139863630
NCBI 1000 Genomes Browser:
rs139863630
Molecular consequence:
  • NM_000448.3:c.2009C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377277.1:c.2009C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377278.1:c.2009C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377279.1:c.2009C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377280.1:c.2009C>T - 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
SCV001231680Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 28, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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, SCV001231680.4

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 670 of the RAG1 protein (p.Thr670Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 860379). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024