Submissions for variant NM_000022.4(ADA):c.43C>G (p.His15Asp)

gnomAD frequency: 0.00001  dbSNP: rs121908725

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429669	SCV000516533	pathogenic	not provided	2015-04-09	criteria provided, single submitter	clinical testing	One in vitro functional study demonstrated that the presence of the H15D variant results in no detectable ADAactivity (Santisteban et al., 1995). A second in vitro functional study demonstrated that the presence of theH15D variant results in very low expressed ADA activity in comparison to wild-type (Arredondo-Vegaet al., 1998) The H15D variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. Therefore, we interpret H15D as a pathogenic variant.
Counsyl	RCV000059102	SCV000797723	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2018-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000059102	SCV000894220	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000059102	SCV001223002	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 15 of the ADA protein (p.His15Asp). 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 missense change has been observed in individual(s) with ADA-SCID (PMID: 7599635, 26376800, 27129325). ClinVar contains an entry for this variant (Variation ID: 68263). 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 ADA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000059102	SCV001977523	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000059102	SCV004211605	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-03-04	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059102	SCV000090626	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
Natera, Inc.	RCV000059102	SCV002095340	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-06-30	no assertion criteria provided	clinical testing