NM_000304.4(PMP22):c.434T>G (p.Leu145Arg) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 27, 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:: RCV001351428.3

Allele description [Variation Report for NM_000304.4(PMP22):c.434T>G (p.Leu145Arg)]

NM_000304.4(PMP22):c.434T>G (p.Leu145Arg)

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.434T>G (p.Leu145Arg)

HGVS:

NC_000017.11:g.15230966A>C
NG_007949.1:g.39362T>G
NM_000304.4:c.434T>GMANE SELECT
NM_001281455.2:c.434T>G
NM_001281456.2:c.434T>G
NM_153321.3:c.434T>G
NM_153322.3:c.434T>G
NP_000295.1:p.Leu145Arg
NP_001268384.1:p.Leu145Arg
NP_001268385.1:p.Leu145Arg
NP_696996.1:p.Leu145Arg
NP_696997.1:p.Leu145Arg
LRG_263:g.39362T>G
NC_000017.10:g.15134283A>C
NR_104017.2:n.529T>G
NR_104018.2:n.429T>G

Protein change:

L145R

Links:

dbSNP: rs1906263385

NCBI 1000 Genomes Browser:

rs1906263385

Molecular consequence:

NM_000304.4:c.434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281455.2:c.434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281456.2:c.434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153321.3:c.434T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153322.3:c.434T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_104017.2:n.529T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104018.2:n.429T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001545893	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001545893

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 27, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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 Invitae, SCV001545893.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt PMP22 protein function. This variant has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1046822). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 145 of the PMP22 protein (p.Leu145Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine.

#	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: Mar 5, 2024

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