ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.1337C>A (p.Pro446His) (rs755964863)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726681 SCV000619985 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing The P446H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P446H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P446H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S447P, S448P, t450S) have been reported in the Human Gene Mutation Database in association with ADSL deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726681 SCV000702089 uncertain significance not provided 2016-09-26 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000785042 SCV000923595 uncertain significance Adenylosuccinate lyase deficiency 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV000785042 SCV001205346 uncertain significance Adenylosuccinate lyase deficiency 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 446 of the ADSL protein (p.Pro446His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs755964863, ExAC 0.02%). This variant has not been reported in the literature in individuals with ADSL-related conditions. ClinVar contains an entry for this variant (Variation ID: 451308). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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