NM_000304.4(PMP22):c.481T>C (p.Ter161Arg) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 18, 2021
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:: RCV001993005.4

Allele description [Variation Report for NM_000304.4(PMP22):c.481T>C (p.Ter161Arg)]

NM_000304.4(PMP22):c.481T>C (p.Ter161Arg)

Gene:

PMP22:peripheral myelin protein 22 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p12

Genomic location:

Preferred name:

NM_000304.4(PMP22):c.481T>C (p.Ter161Arg)

HGVS:

NC_000017.11:g.15230919A>G
NG_007949.1:g.39409T>C
NM_000304.4:c.481T>CMANE SELECT
NM_001281455.2:c.481T>C
NM_001281456.2:c.481T>C
NM_153321.3:c.481T>C
NM_153322.3:c.481T>C
NP_000295.1:p.Ter161Arg
NP_001268384.1:p.Ter161Arg
NP_001268385.1:p.Ter161Arg
NP_696996.1:p.Ter161Arg
NP_696997.1:p.Ter161Arg
LRG_263:g.39409T>C
NC_000017.10:g.15134236A>G
NR_104017.2:n.576T>C
NR_104018.2:n.476T>C

Links:

dbSNP: rs2150664495

NCBI 1000 Genomes Browser:

rs2150664495

Molecular consequence:

NR_104017.2:n.576T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104018.2:n.476T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000304.4:c.481T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001281455.2:c.481T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_001281456.2:c.481T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_153321.3:c.481T>C - stop lost - [Sequence Ontology: SO:0001578]
NM_153322.3:c.481T>C - stop lost - [Sequence Ontology: SO:0001578]

Condition(s)

Name:: Charcot-Marie-Tooth disease, type I (CMT1)
Synonyms:: Charcot-Marie-Tooth Neuropathy Type 1; Hereditary Motor and Sensory Neuropathy 1; Charcot-Marie-Tooth, Type 1
Identifiers:: MONDO: MONDO:0019011; MedGen: C0751036

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002229028	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32412171, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002229028

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 18, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel homozygous variant extending the peripheral myelin protein 22 by 9 amino acids causes early-onset Charcot-Marie-Tooth disease with predominant severe sensory ataxia.

Zambon AA, Pitt M, Laurà M, Polke JM, Reilly MM, Muntoni F.

J Peripher Nerv Syst. 2020 Sep;25(3):303-307. doi: 10.1111/jns.12386. Epub 2020 May 29.

PubMed [citation]

PMID:: 32412171

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002229028.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the PMP22 protein in which other variant(s) (p.*161Trpext*10) have been observed in individuals with PMP22-related conditions (PMID: 32412171). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. This protein extension has been observed in individual(s) with clinical features of PMP22-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the PMP22 mRNA. It is expected to extend the length of the PMP22 protein by 10 additional amino acid residues.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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