NM_000022.4(ADA):c.516C>A (p.Tyr172Ter) AND Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: May 28, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001263784.10

Allele description [Variation Report for NM_000022.4(ADA):c.516C>A (p.Tyr172Ter)]

NM_000022.4(ADA):c.516C>A (p.Tyr172Ter)

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.516C>A (p.Tyr172Ter)

Other names:

NM_000022.4(ADA):c.516C>A; p.Tyr172Ter

HGVS:

NC_000020.11:g.44624292G>T
NG_007385.1:g.32444C>A
NM_000022.4:c.516C>AMANE SELECT
NM_001322050.2:c.111C>A
NM_001322051.2:c.516C>A
NP_000013.2:p.Tyr172Ter
NP_001308979.1:p.Tyr37Ter
NP_001308980.1:p.Tyr172Ter
LRG_16:g.32444C>A
NC_000020.10:g.43252933G>T
NR_136160.2:n.608C>A

Protein change:

Y172*

Links:

dbSNP: rs748810619

NCBI 1000 Genomes Browser:

rs748810619

Molecular consequence:

NR_136160.2:n.608C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000022.4:c.516C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001322050.2:c.111C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001322051.2:c.516C>A - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

Clear Turn Off Turn On

histone H2A type 1-A [Homo sapiens]
histone H2A type 1-A [Homo sapiens]
gi|25092737|ref|NP_734466.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001441877	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Jun 15, 2019)	unknown	clinical testing	Citation Link,
SCV004213434	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 1, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004238416	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004492394	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26255240, 26376800, 28492532
SCV005375392	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications ADA V1.0.0)	Likely Pathogenic (May 28, 2024)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Spectrum of mutations in a cohort of UK patients with ADA deficient SCID: Segregation of genotypes with specific ethnicities.

Adams SP, Wilson M, Harb E, Fairbanks L, Xu-Bayford J, Brown L, Kearney L, Madkaikar M, Bobby Gaspar H.

Clin Immunol. 2015 Dec;161(2):174-9. doi: 10.1016/j.clim.2015.08.001. Epub 2015 Aug 5.

PubMed [citation]

PMID:: 26255240

See all PubMed Citations (4)

Details of each submission

From Myriad Genetics, Inc., SCV001441877.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004213434.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV004238416.1

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

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004492394.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Tyr172*) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is present in population databases (rs748810619, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ADA-related conditions. ClinVar contains an entry for this variant (Variation ID: 983781). 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

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV005375392.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.516C>A (p.Tyr172Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The filtering allele frequency (the upper threshold of the 95% CI of 5/86250) of the c.516C>A variant in ADA is 0.00002194 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification. In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_supporting.

#	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 26, 2024

ClinVar

Relating variation to medicine