Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038619 | SCV000062297 | uncertain significance | not specified | 2012-08-14 | criteria provided, single submitter | clinical testing | The Arg1506Cys variant in ABCC9 has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. Additional information is n eeded to fully assess the clinical significance of this variant. |
| Ambry Genetics | RCV000618677 | SCV000736969 | uncertain significance | Cardiovascular phenotype | 2024-03-15 | criteria provided, single submitter | clinical testing | The p.R1506C variant (also known as c.4516C>T), located in coding exon 38 of the ABCC9 gene, results from a C to T substitution at nucleotide position 4516. The arginine at codon 1506 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001038743 | SCV001202232 | uncertain significance | Dilated cardiomyopathy 1O | 2023-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1506 of the ABCC9 protein (p.Arg1506Cys). This variant is present in population databases (rs397517191, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 45416). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC9 protein function with a positive predictive value of 95%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000038619 | SCV001442788 | likely benign | not specified | 2020-10-08 | criteria provided, single submitter | clinical testing | Variant summary: ABCC9 c.4516C>T (p.Arg1506Cys) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) 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 9.9e-05 in 282042 control chromosomes, predominantly at a frequency of 0.00064 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 41 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Dilated Cardiomyopathy phenotype (1.6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.4516C>T has been reported in the literature in at least one individual affected with dilated cardiomyopathy along with several variants in other genes (Pugh_2014). This report however, does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |