ClinVar Miner

Submissions for variant NM_007126.5(VCP):c.2222G>A (p.Arg741His)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002428099 SCV002730206 uncertain significance Inborn genetic diseases 2020-12-29 criteria provided, single submitter clinical testing The p.R741H variant (also known as c.2222G>A), located in coding exon 16 of the VCP gene, results from a G to A substitution at nucleotide position 2222. The arginine at codon 741 is replaced by histidine, an amino acid with highly similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV005227752 SCV005868056 uncertain significance Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 741 of the VCP protein (p.Arg741His). This variant is present in population databases (rs760411781, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with VCP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1787954). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VCP protein function with a negative predictive value of 80%. 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.

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