ClinVar Miner

Submissions for variant NM_007126.5(VCP):c.476G>A (p.Arg159His)

gnomAD frequency: 0.00001  dbSNP: rs121909335
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000276565 SCV000329984 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing The R159H variant in the VCP gene has been reported previously in association with inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as both sporadic and familial forms of amyotrophic lateral sclerosis (Haubenberger et al., 2005; Ayaki et al., 2014; van der Zee et al., 2009). In vitro expression studies of the R159H variant in SH-SY5Y cells showed a statistically significant increase in the percentage of cells with cytoplasmic TDP-43; translocation of TDP-43 to the cytoplasm and aggregation in the cytoplasm has previously been reported as a feature of VCP-related ALS (Ayaki et al., 2014). The R159H variant is observed in 1/22300 alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). Although the R159H variant is a conservative amino acid substitution, it occurs in the four-stranded b barrel in the CDC48 domain, a critical functional domain (Hubbers et al., 2007). We interpret R159H as a pathogenic variant.
Eurofins Ntd Llc (ga) RCV000276565 SCV000709188 pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing
Invitae RCV000639653 SCV000761233 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia 2024-01-25 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 159 of the VCP protein (p.Arg159His). This variant is present in population databases (rs121909335, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD) (PMID: 16247064, 19225410, 19704082, 22078486, 24829604, 26555887). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8474). 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 not expected to disrupt VCP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects VCP function (PMID: 22270372, 25492614, 26555887, 27226613). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000276565 SCV001248047 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000276565 SCV002020857 pathogenic not provided 2023-04-28 criteria provided, single submitter clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV003335021 SCV004045882 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 2023-01-23 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000276565 SCV004229423 pathogenic not provided 2022-10-26 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). It is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant has been identified in multiple unrelated individuals with clinical features of FTD/ALS as well as IBMPFD. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMIDs: 22270372, 27226613, 25492614) The variant is located in a region that is considered important for protein function and/or structure.
OMIM RCV000008995 SCV000029209 pathogenic Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 2009-08-25 no assertion criteria provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000276565 SCV001926641 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000276565 SCV001954556 pathogenic not provided no assertion criteria provided clinical testing

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