NM_000448.3(RAG1):c.2143del (p.Val715fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 10, 2023
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:: RCV003779083.2

Allele description [Variation Report for NM_000448.3(RAG1):c.2143del (p.Val715fs)]

NM_000448.3(RAG1):c.2143del (p.Val715fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000448.3(RAG1):c.2143del (p.Val715fs)

HGVS:

NC_000011.10:g.36575447del
NG_007528.1:g.12435del
NM_000448.3:c.2143delMANE SELECT
NM_001377277.1:c.2143del
NM_001377278.1:c.2143del
NM_001377279.1:c.2143del
NM_001377280.1:c.2143del
NP_000439.1:p.Val715Cysfs
NP_000439.2:p.Val715fs
NP_001364206.1:p.Val715fs
NP_001364207.1:p.Val715fs
NP_001364208.1:p.Val715fs
NP_001364209.1:p.Val715fs
LRG_98t1:c.2143del
LRG_98:g.12435del
LRG_98p1:p.Val715Cysfs
NC_000011.9:g.36596997del
NM_000448.2:c.2143delG

Protein change:

V715fs

Molecular consequence:

NM_000448.3:c.2143del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377277.1:c.2143del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377278.1:c.2143del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377279.1:c.2143del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377280.1:c.2143del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004588421	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2023)	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

SCV004588421

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 10, 2023)

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, SCV004588421.1

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

Description

This sequence change creates a premature translational stop signal (p.Val715Cysfs*35) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 329 amino acid(s) of the RAG1 protein. This variant is present in population databases (rs773194976, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RAG1-related conditions. This variant disrupts a region of the RAG1 protein in which other variant(s) (p.His994Arg) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as 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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