NM_000448.3(RAG1):c.256_257del (p.Lys86fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 30, 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:: RCV000282657.9

Allele description [Variation Report for NM_000448.3(RAG1):c.256_257del (p.Lys86fs)]

NM_000448.3(RAG1):c.256_257del (p.Lys86fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

11p12

Genomic location:

Preferred name:

NM_000448.3(RAG1):c.256_257del (p.Lys86fs)

Other names:

NM_000448.3(RAG1):c.256_257del; p.Lys86fs

HGVS:

NC_000011.10:g.36573560_36573561del
NG_007528.1:g.10548_10549del
NM_000448.3:c.256_257delMANE SELECT
NM_001377277.1:c.256_257del
NM_001377278.1:c.256_257del
NM_001377279.1:c.256_257del
NM_001377280.1:c.256_257del
NP_000439.2:p.Lys86fs
NP_001364206.1:p.Lys86fs
NP_001364207.1:p.Lys86fs
NP_001364208.1:p.Lys86fs
NP_001364209.1:p.Lys86fs
LRG_98:g.10548_10549del
NC_000011.9:g.36595110_36595111del
NM_000448.2:c.256_257delAA
NM_000448.3:c.256_257del

Links:

OMIM: 179615.0013; dbSNP: rs772962160

NCBI 1000 Genomes Browser:

rs772962160

Molecular consequence:

NM_000448.3:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377277.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377278.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377279.1:c.256_257del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001377280.1:c.256_257del - 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
SCV000638115	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9630231, 22424479, 23085344, 24290284, 10891452, 24418478, 25516070, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638115

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

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

Partial V(D)J recombination activity leads to Omenn syndrome.

Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, Gatta LB, Ochs HD, Schwarz K, Notarangelo LD, Vezzoni P, Spanopoulou E.

Cell. 1998 May 29;93(5):885-96.

PubMed [citation]

PMID:: 9630231

Novel mutatıons and diverse clinical phenotypes in recombinase-activating gene 1 deficiency.

Kutukculer N, Gulez N, Karaca NE, Aksu G, Berdeli A.

Ital J Pediatr. 2012 Mar 16;38:8. doi: 10.1186/1824-7288-38-8.

PubMed [citation]

PMID:: 22424479
PMCID:: PMC3394211

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000638115.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Lys86Valfs*33) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 958 amino acid(s) of the RAG1 protein. This variant is present in population databases (rs772962160, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Omenn syndrome or severe combined immunodeficiency (PMID: 9630231, 22424479, 23085344, 24290284, 25516070). ClinVar contains an entry for this variant (Variation ID: 285045). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RAG1 function (PMID: 10891452, 24418478, 25516070). 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: Oct 8, 2024

ClinVar

Relating variation to medicine