ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.305T>C (p.Leu102Pro) (rs374659816)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767047 SCV000576711 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing The L102P variant of uncertain significance in the ABCC9 gene has not been published as pathogenic or been reported as benign to our knowledge. The L102P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and 2/3 in silico algorithms predict this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the L102P variant. Furthermore, the L102P variant was observed in 7/10,404 alleles from individuals of African ancestry and 4/8,652 alleles from individuals of East Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016).
Invitae RCV000558108 SCV000639231 uncertain significance Dilated cardiomyopathy 1O 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 102 of the ABCC9 protein (p.Leu102Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs374659816, ExAC 0.07%) but has not been reported in the literature in individuals with an ABCC9-related disease. ClinVar contains an entry for this variant (Variation ID: 426305). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000490221 SCV000710888 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing The p.Leu102Pro variant in ABCC9 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.08% (19/24034) of African chr omosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitut; dbSNP rs374659816). Computational prediction tools and conservation anal ysis do not provide strong support for or against an impact to the protein. In s ummary, the clinical significance of the p.Leu102Pro variant is uncertain.

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