ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.320T>C (p.Leu107Pro) (rs121908739)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255602 SCV000321379 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing The L107P variant in the ADA gene has been reported previously in association with adenosine deaminase deficiency (Hirschhorn et al., 1990; Santisteban et al., 1995). The variant is observed in 9/33582 (0.0268%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). L107P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies have shown L107P significantly reduces the activity of the ADA protein (Arredondo-Vega et al., 1998). We consider this variant to be pathogenic.
Invitae RCV000002042 SCV000644840 pathogenic Severe combined immunodeficiency due to ADA deficiency 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 107 of the ADA protein (p.Leu107Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs121908739, ExAC 0.04%). This variant has been reported in combination with other ADA variants in several individuals affected with adenosine deaminase deficiency (PMID: 2166947, 2758612, 9225964, 7599635). ClinVar contains an entry for this variant (Variation ID: 1965). Experimental studies have shown or reported that this missense change exhibits severely diminished adenosine deaminase activity (PMID: 9758612, 9361033, 7599635). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255602 SCV000704676 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000002042 SCV000894219 likely pathogenic Severe combined immunodeficiency due to ADA deficiency 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194145 SCV001363445 pathogenic Severe Combined Immune Deficiency 2019-09-16 criteria provided, single submitter clinical testing Variant summary: ADA c.320T>C (p.Leu107Pro) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251456 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency Syndrome (7.2e-05 vs 0.0016), allowing no conclusion about variant significance. The variant, c.320T>C, has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome (Hirschhorn_1990, Santisteban_1995, Arredondo-Vega_1998). These data indicate that the variant is very likely to be associated with disease. Expression of the variant also showed <10% enzyme activity in experimental studies (Arredondo-Vega_1998). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000002042 SCV000022200 pathogenic Severe combined immunodeficiency due to ADA deficiency 1990-08-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002042 SCV000090622 not provided Severe combined immunodeficiency due to ADA deficiency no assertion provided not provided
Counsyl RCV000002042 SCV000795157 likely pathogenic Severe combined immunodeficiency due to ADA deficiency 2017-10-27 no assertion criteria provided clinical testing

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