Submissions for variant NM_000022.4(ADA):c.454C>A (p.Leu152Met)

gnomAD frequency: 0.00002  dbSNP: rs121908728

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000059105	SCV004098707	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-10-10	reviewed by expert panel	curation	The c.454C>A (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Leu by Met at amino acid 152. The filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.0006937 for South Asian chromosomes by gnomAD v 2.1.1, which is bigger than the ClinGen SCID VCEP threshold (0.0001742). So, PM2 is not met. The variant has been reported to segregate with SCID in 02 affected members (proband +1) from one family. LOD score: 0.6 = PP1_supporting. At least one patient (P6, PMID: 29744787) with this variant displayed: * Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met: 0.5 points, * Reduced ADA enzyme activity in patient cells (see table 2) 1 point, and * Lymphocyte count partially corrected by ADA enzyme replacement therapy: 1 point = TOTAL: 2.5 points, which is highly specific for SCID (PP4_moderate, PMID: 29744787.) In summary, this variant meets the criteria to be classified as VUS for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP1_Supporting, PP4_Moderate (SCID VCEP specifications version 1.0).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731271	SCV000918391	likely pathogenic	Severe combined immunodeficiency disease	2022-03-24	criteria provided, single submitter	clinical testing	Variant summary: ADA c.454C>A (p.Leu152Met) results in a conservative amino acid change located in the Adenosine/AMP deaminase domain (IPR001365) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 209700 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency Syndrome (0.00016 vs 0.0016), allowing no conclusion about variant significance. c.454C>A has been reported in the literature in individuals affected with late-onset adenosine deaminase (ADA) deficiency (Cagdas_2018) and in a healthy homozygous individual with partial ADA deficiency (Hirschhorn 1997). These data indicate that the variant is likely to be associated with disease. Several publications report that ADA enzymatic activity could not be detected in the red cells with the variant (Hirschhorn_1997, Cagdas_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=6, VUS n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059105	SCV001233960	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 152 of the ADA protein (p.Leu152Met). This variant is present in population databases (rs121908728, gnomAD 0.1%). This missense change has been observed in individual(s) with delayed onset adenosine deaminase deficiency (PMID: 9225964, 29744787). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1979). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ADA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 9225964). For these reasons, this variant has been classified as Pathogenic.
Pars Genome Lab	RCV000059105	SCV001652853	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001531958	SCV001747310	likely pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001531958	SCV001755475	likely pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000059105	SCV001810253	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000059105	SCV002021298	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-12-29	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000059105	SCV002573132	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.46). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001979). A different missense change at the same codon (p.Leu152Pro) has been reported to be associated with ADA-related disorder (PMID: 31031743). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000059105	SCV004216682	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-03-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001531958	SCV005201836	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrate a damaging effect of L152M on ADA activity (PMID: 9225964); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14499267, 29744787, 34426522, 9225964, 36964972, 32445296)
Neuberg Centre For Genomic Medicine, NCGM	RCV000059105	SCV005849169	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.454C>A(p.Leu152Met) variant in ADA gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Severe Combined Immunodeficiency Syndrome / adenosine deaminase (ADA) deficiency (Cagdas D, et al., 2018; Firtina S, et al., 2020; 2020 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference., 2020). This variant has also been observed to segregate with disease in related individuals. Functional expression studies of this variant showed that it leads to less enzymatic activity. However, it was concluded that p.Leu152Met variant will result in disease in homozygous individuals challenged by severe environmental stresses, or in heterozygous individuals when combined with another null variant (Hirschhorn R, et al., 1997). The p.Leu152Met variant is present with allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on ADA gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 152 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another reportable variant in ADA gene, the molecular diagnosis is not confirmed.
OMIM	RCV000002056	SCV000022214	pathogenic	Partial adenosine deaminase deficiency	1997-07-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059105	SCV000090629	not provided	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency		no assertion provided	not provided
Counsyl	RCV000059105	SCV000798611	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2018-03-14	flagged submission	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000059105	SCV000895245	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2018-10-31	flagged submission	clinical testing