Hereditary neuropathy or pain disorder

Gene: VCP

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown following NHS Genomic Medicine Service approval.

Created: 10 Oct 2023, 6:06 p.m. | Last Modified: 10 Oct 2023, 6:06 p.m.

Panel Version: 3.58

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Gonzalez et al. (2014) report the first association between VCP and CMT2. The group reports a family of 5 individuals affected with CMT2, who carry a novel missense variant c.553C>T (p.Glu185Lys). 3 unaffected family members do not carry this variant. Functional studies performed by the group show that this variant leads to an increase in LC3II levels, consistent with the previously defined disruption in autophagosome maturation by VCP disease mutations. Jerath et al. (2015) report a man with CMT2 who carries a missense variant c.290 C>T (p.Gly97Glu). Functional studies showed that this variant has increased ATPase activity similar to other VCP mutants. Gite et al. (2020) report a proband, his father and his fraternal twin, all diagnosed with CMT2. The clinical diagnosis of CMT2 was based on the observations of distal amyotrophy and mild sensory abnormalities, and electrophysiological evidence of chronic progressive axonopathy in the proband. WES identifies a novel missense VUS variant in the 3 affected individuals, c.511A>C (p.Ser171Arg), which localises to the N-terminal domain. The group did not perform any functional studies, and they also did not perform genetic analysis in the probands 2 unaffected sisters. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance. Disease severity varies among different individuals, even from the same family.

Created: 20 Jan 2023, 11:16 a.m. | Last Modified: 20 Jan 2023, 11:16 a.m.

Panel Version: 2.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Charcot-Marie-Tooth disease, type 2Y, OMIM:616687

Publications

• 25125609
• 32165109
• 25878907

Green List (high evidence)

Third family reported with phenotypic variability between the proband, his brother, and father. - The clinical diagnosis of CMT2 was based on the observations of distal amyotrophy and mild sensory abnormalities, and electrophysiological evidence of chronic progressive axonopathy in the proband. - The proband's brother had fewer clinical signs of CMT2 compared to the proband and his father, with mild hand weakness and length-dependent sensory deficits with no lower extremity weakness. - The findings in the father reflected a novel phenotypic partial synthesis of ALS-like (i.e., UMN and LMN) in conjunction with CMT2-like (motor and sensory) phenomena.

Created: 9 Aug 2021, 10:58 a.m. | Last Modified: 9 Aug 2021, 10:58 a.m.

Panel Version: 1.37

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Charcot-Marie-Tooth disease, type 2Y, MIM# 616687

Publications

• 25125609
• 25878907
• 32165109

Mode of pathogenicity
Other

Only two families reported, unclear if definitely causes CMT

Created: 9 May 2019, 12:12 p.m.

Green List (high evidence)

Comment on list classification: Downgraded from Green to Amber from recommendation from Alex Rossor - only two published cases of VCP and neuropathy. P.Glu185Lys is absent form GNOMAD but p.Glu185Asp is present 4 times. I don’t think there have been any more cases. Might it be better as Amber for neuropathy?

Created: 13 Dec 2019, 1:36 p.m. | Last Modified: 13 Dec 2019, 1:36 p.m.

Panel Version: 0.106

Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: ALS+/-FTD; unclear whether also causes CMT - Amber? Very rare but I think include as Green as reasonable evidence for distal myopathy/neuropathy

Created: 7 Dec 2019, 12:03 a.m. | Last Modified: 7 Dec 2019, 12:03 a.m.

Panel Version: 0.86

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 10:25 p.m. | Last Modified: 6 Dec 2019, 10:25 p.m.

Panel Version: 0.84

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

Red List (low evidence)

Two families

Created: 29 Apr 2019, 9:20 a.m.

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Is on the Charcot-Marie- Tooth disease type 2 / Intermediate CMT NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual.

Created: 10 Jun 2016, 1:10 p.m.

Comment on list classification: Gene added by a reviewer, and rated green by a second reviewer.

Created: 9 May 2016, 10:10 a.m.