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NM_004279.3(PMPCB):c.1154+5G>C AND PMPCB-related ataxia

Germline classification:
Likely pathogenic (1 submission)
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003329563.2

Allele description [Variation Report for NM_004279.3(PMPCB):c.1154+5G>C]

NM_004279.3(PMPCB):c.1154+5G>C

Gene:
PMPCB:peptidase, mitochondrial processing subunit beta [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q22.1
Genomic location:
Preferred name:
NM_004279.3(PMPCB):c.1154+5G>C
HGVS:
  • NC_000007.14:g.103310480G>C
  • NM_004279.3:c.1154+5G>CMANE SELECT
  • NC_000007.13:g.102950927G>C
Molecular consequence:
  • NM_004279.3:c.1154+5G>C - intron variant - [Sequence Ontology: SO:0001627]
Functional consequence:
sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

Condition(s)

Name:
PMPCB-related ataxia
Identifiers:

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004036150Tetreault Lab, University of Montreal Hospital Research Centre (CRCHUM)
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenicgermlineresearch

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedresearch

Details of each submission

From Tetreault Lab, University of Montreal Hospital Research Centre (CRCHUM), SCV004036150.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearchnot provided
2not providednot providednot providednot providedresearchnot provided

Description

"Further validation and case number will be required to confirm novel association of PMPCB with ataxia."

DOI [ID: 10.1093/brain/awv362]

Description

This variant, reported with low allele frequency (gnomAD AF = 4.91e-5), causes alternative splicing of PMPCB, the beta subunit of the essential mitochondrial processing protease. Exon 9 splice donor loss was predicted in silico to cause exon 9 skipping, which was validated by PCR and long-read sequencing. Alternative splicing causes the loss of two α-helix and two β-sheets inside the protein and a likely loss-of-function. In silico predictions support loss-of-function of the allele (CADD = 23.1; SIFT = 0.93; Polyphen2 = 0.996). qPCR expression suggests decrease of mRNA levels and possible nonsense-mediated decay. The protease is essential for processing of proteins such as FXN and PINK1. Loss-of-function of the subunit is expected to cause an ataxia similar to what is observed with PMPCA loss-of-function. For these reason, the variant is interpreted as likely pathogenic in the context of atypical episodic ataxia.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not provideddiscovery1not providednot providednot provided
2germlineyesnot providedPeripheral blood mononuclear cellsvalidationnot providednot providednot providednot provided

Last Updated: Jun 23, 2024