ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.911T>G (p.Leu304Arg)

gnomAD frequency: 0.00002  dbSNP: rs199422327
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000002035 SCV001220995 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the ADA protein (p.Leu304Arg). This variant is present in population databases (rs199422327, gnomAD 0.008%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 46025, 1284479, 17185467). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1006T>G. ClinVar contains an entry for this variant (Variation ID: 1958). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 3007108). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV000002035 SCV002060121 likely pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2021-11-10 criteria provided, single submitter clinical testing NM_000022.2(ADA):c.911T>G(L304R) is a missense variant classified as likely pathogenic in the context of adenosine deaminase deficiency. L304R has been observed in cases with relevant disease (PMID: 17185467, 1346349). Functional assessments of this variant are available in the literature (PMID: 3007108). L304R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000022.2(ADA):c.911T>G(L304R) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics RCV000002035 SCV004213534 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2023-03-24 criteria provided, single submitter clinical testing
OMIM RCV000002035 SCV000022193 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 1986-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000002035 SCV002095301 likely pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency 2021-03-05 no assertion criteria provided clinical testing

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