NM_000448.3(RAG1):c.1981_1983del (p.Met661del) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 8, 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:: RCV001234668.8

Allele description [Variation Report for NM_000448.3(RAG1):c.1981_1983del (p.Met661del)]

NM_000448.3(RAG1):c.1981_1983del (p.Met661del)

Gene:

RAG1:recombination activating 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000448.3(RAG1):c.1981_1983del (p.Met661del)

HGVS:

NC_000011.10:g.36575285_36575287del
NG_007528.1:g.12273_12275del
NM_000448.3:c.1981_1983delMANE SELECT
NM_001377277.1:c.1981_1983del
NM_001377278.1:c.1981_1983del
NM_001377279.1:c.1981_1983del
NM_001377280.1:c.1981_1983del
NP_000439.2:p.Met661del
NP_001364206.1:p.Met661del
NP_001364207.1:p.Met661del
NP_001364208.1:p.Met661del
NP_001364209.1:p.Met661del
LRG_98t1:c.1981_1983del
LRG_98:g.12273_12275del
NC_000011.9:g.36596835_36596837del
NM_000448.2:c.1981_1983del

Protein change:

M661del

Links:

dbSNP: rs774103837

NCBI 1000 Genomes Browser:

rs774103837

Molecular consequence:

NM_000448.3:c.1981_1983del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001377277.1:c.1981_1983del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001377278.1:c.1981_1983del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001377279.1:c.1981_1983del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001377280.1:c.1981_1983del - inframe_deletion - [Sequence Ontology: SO:0001822]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001407325	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001407325

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 8, 2024)

germline

clinical testing

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

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

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, SCV001407325.5

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

Description

This variant, c.1981_1983del, results in the deletion of 1 amino acid(s) of the RAG1 protein (p.Met661del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774103837, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of severe combined immunodeficiency (Invitae). 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: 961035). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

#	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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