NM_000022.4(ADA):c.1A>G (p.Met1Val) AND Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 10, 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:: RCV001378051.7

Allele description [Variation Report for NM_000022.4(ADA):c.1A>G (p.Met1Val)]

NM_000022.4(ADA):c.1A>G (p.Met1Val)

Genes:

LOC107303343:adenosine deaminase intronic regulatory elements [Gene]
ADA:adenosine deaminase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q13.12

Genomic location:

Preferred name:

NM_000022.4(ADA):c.1A>G (p.Met1Val)

HGVS:

NC_000020.11:g.44651607T>C
NG_007385.1:g.5129A>G
NG_046759.1:g.22704T>C
NM_000022.4:c.1A>GMANE SELECT
NM_001322050.2:c.-289A>G
NM_001322051.2:c.1A>G
NP_000013.2:p.Met1Val
NP_001308980.1:p.Met1Val
LRG_16:g.5129A>G
NC_000020.10:g.43280248T>C
NR_136160.2:n.93A>G

Protein change:

M1V

Links:

dbSNP: rs1363043396

NCBI 1000 Genomes Browser:

rs1363043396

Molecular consequence:

NM_001322050.2:c.-289A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000022.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001322051.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000022.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001322051.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136160.2:n.93A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
Synonyms:: ADA-SCID; SCID DUE TO ADA DEFICIENCY, EARLY-ONSET; ADA deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007064; MedGen: C1863236; Orphanet: 277; OMIM: 102700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001575534	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 10, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7599635, 26376800, 27129325, 31681265, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001575534

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 10, 2022)

germline

clinical testing

PubMed (5)
[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

Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site.

Santisteban I, Arredondo-Vega FX, Kelly S, Debre M, Fischer A, Pérignon JL, Hilman B, elDahr J, Dreyfus DH, Gelfand EW, et al.

Hum Mutat. 1995;5(3):243-50.

PubMed [citation]

PMID:: 7599635

Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience.

Baffelli R, Notarangelo LD, Imberti L, Hershfield MS, Serana F, Santisteban I, Bolda F, Porta F, Lanfranchi A.

J Clin Immunol. 2015 Oct;35(7):624-37. doi: 10.1007/s10875-015-0191-z. Epub 2015 Sep 16.

PubMed [citation]

PMID:: 26376800

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575534.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. This variant disrupts the p.His15 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7599635, 26376800, 27129325). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1066924). Disruption of the initiator codon has been observed in individual(s) with primary immunodeficiency (PMID: 31681265). 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 sequence change affects the initiator methionine of the ADA mRNA. The next in-frame methionine is located at codon 52.

#	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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