ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.47A>G (p.Asn16Ser) (rs727502877)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458476 SCV000551686 uncertain significance Dilated cardiomyopathy 1O 2016-09-26 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 16 of the ABCC9 protein (p.Asn16Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs727502877, ExAC 0.01%) but has not been reported in the literature in individuals with a ABCC9-related disease. ClinVar contains an entry for this variant (Variation ID: 162700). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but 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 RCV000150126 SCV000196971 uncertain significance not specified 2013-11-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Asn16Ser varian t in ABCC9 has not been previously reported in individuals with cardiomyopathy a nd was absent from large population studies. Asparagine (Asn) at position 16 is poorly conserved in evolution and at least 1 species (shrew, a mammal) carries t he variant amino acid (serine, Ser), raising the possibility that this change ma y be tolerated. Additional computational analyses (biochemical amino acid proper ties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact t he protein, though this information is not predictive enough to rule out pathoge nicity. In summary, the lack of evolutionary conservation suggests that this var iant may be more likely benign, but additional information is needed to fully as sess its clinical significance.

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