ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2852C>G (p.Pro951Arg) (rs368570586)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038818 SCV000062496 likely benign not specified 2010-11-16 criteria provided, single submitter clinical testing Pro951Arg in exon 19 of VCL: The Pro951Arg variant has not been reported in the literature and has not been identified in over 500 Caucasian chromosomes tested by our laboratory. In addition, proline (Pro) at position 951 is highly conserve d across evolutionary distant species, suggesting that a change at this position may not be tolerated. However, this variant was observed to not segregate with disease in one family (one affected individual was negative). Although this cou ld be caused by a second, undetected variant in this family it is more likely th at the Pro951Arg variant is insufficient to cause disease in isolation.
GeneDx RCV000766998 SCV000236477 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing The P951R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this variant has been previously identified in one other unrelated individual referred for DCM genetic testing at GeneDx, segregation data is absent. This variant was not observed with any significant frequency 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 P951R 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. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Furthermore, the P951R variant has been classified in ClinVar as a likely benign variant by another clinical laboratory based on the lack of segregation with disease in an affected relative (ClinVar SCV000062496.4; Landrum et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.

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