Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000463998 | SCV000548795 | uncertain significance | Dilated cardiomyopathy 1W | 2023-12-04 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 399 of the VCL protein (p.Asn399His). This variant is present in population databases (rs377228795, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 408949). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| Ambry Genetics | RCV002339158 | SCV002644917 | uncertain significance | Cardiovascular phenotype | 2022-12-01 | criteria provided, single submitter | clinical testing | The p.N399H variant (also known as c.1195A>C), located in coding exon 10 of the VCL gene, results from an A to C substitution at nucleotide position 1195. The asparagine at codon 399 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002480406 | SCV002783594 | uncertain significance | Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15 | 2022-05-06 | criteria provided, single submitter | clinical testing | |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786266 | SCV000925017 | uncertain significance | not provided | 2017-01-09 | no assertion criteria provided | provider interpretation | Given the limited evidence to associate VCL with dilated cardiomyopathy and the absence of case data available for this variant consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data available for this variant. According to the test report, "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." The asparagine at codon 399 is conserved across species, as are neighboring amino acids. The variant was reported online in 15 of 141,273 individuals (MAF=0.0053%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 7 of 9,468 individuals of East Asian descent (MAF=0.037%), 6 of 15,450 individuals of South Asian descent (MAF=0.019%), 1 of 12,933 individuals of African descent (MAF=0.0039%) and 1 of 18,236 individuals of Latino descent (MAF=0.0027%). Note that the phenotype of the individuals in these datasets is not publicly available. The datasets arecomprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. |