VCV002678205.2 - ClinVar

NM_000448.3(RAG1):c.2918G>A (p.Arg973His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000448.3(RAG1):c.2918G>A (p.Arg973His)

Variation ID: 2678205 Accession: VCV002678205.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p12 11: 36576222 (GRCh38) [ NCBI UCSC ] 11: 36597772 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 30, 2023	Feb 28, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000448.3:c.2918G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000439.2:p.Arg973His	missense
NM_001377277.1:c.2918G>A	NP_001364206.1:p.Arg973His	missense
NM_001377278.1:c.2918G>A	NP_001364207.1:p.Arg973His	missense
NM_001377279.1:c.2918G>A	NP_001364208.1:p.Arg973His	missense
NM_001377280.1:c.2918G>A	NP_001364209.1:p.Arg973His	missense
NC_000011.10:g.36576222G>A
NC_000011.9:g.36597772G>A
NG_007528.1:g.13210G>A
LRG_98:g.13210G>A
LRG_98t1:c.2918G>A	LRG_98p1:p.Arg973His

... more HGVS ... less HGVS

Protein change

R973H

Other names

Canonical SPDI

NC_000011.10:36576221:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RAG1		-	-	GRCh38 GRCh37	836	863

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Combined immunodeficiency due to partial RAG1 deficiency	Likely pathogenic (1)	criteria provided, single submitter	Apr 14, 2023	RCV003472557.1
Combined immunodeficiency with skin granulomas Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	Pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV003779081.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Apr 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined immunodeficiency due to partial RAG1 deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004200511.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Combined immunodeficiency with skin granulomas Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004568677.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 11313270‚ 24290284 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 973 of the RAG1 protein (p.Arg973His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 973 of the RAG1 protein (p.Arg973His). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 11313270). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 11313270). This variant disrupts the p.Arg973 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24290284; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 973 of the RAG1 protein (p.Arg973His). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 11313270). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 11313270). This variant disrupts the p.Arg973 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24290284; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.	Lee YN	The Journal of allergy and clinical immunology	2014	PMID: 24290284
Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome.	Corneo B	Blood	2001	PMID: 11313270

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000448.3(RAG1):c.2918G>A (p.Arg973His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...