ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.1603T>C (p.Tyr535His) (rs397517184)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038586 SCV000062264 uncertain significance not specified 2012-07-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Tyr535His varia nt in ABCC9 has not been reported in the literature nor previously identified by our laboratory. Tyrosine (Tyr) at position 535 is not well conserved in evoluti on (chicken and fish both carry the variant amino acid (His) at this position), suggesting that this change may be tolerated. Other computational analyses (bioc hemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that this variant may not impact the protein, though this information is not predict ive enough to rule out pathogenicity. This variant is more likely benign but add itional data is needed to establish this with confidence.
GeneDx RCV000766938 SCV000532643 uncertain significance not provided 2016-10-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ABCC9 gene. While the Y535H variant has not been published as a pathogenic variant or reported as a benign variant, it has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000062264.4; Landrum et al., 2016). The Y535H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y535H 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is conserved only in mammals and Histidine is the wild type in several species.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000792599 SCV000931905 uncertain significance Dilated cardiomyopathy 1O 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 535 of the ABCC9 protein (p.Tyr535His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs397517184, ExAC 0.01%). This variant has not been reported in the literature in individuals with ABCC9-related conditions. ClinVar contains an entry for this variant (Variation ID: 45389). 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 tolerated, 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.
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000038586 SCV000221407 likely benign not specified 2016-09-28 no assertion criteria provided research

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