NM_000304.4(PMP22):c.215C>G (p.Ser72Trp) AND Charcot-Marie-Tooth disease, type I

Clinical significance:Likely pathogenic (Last evaluated: Aug 15, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000802360.1

Allele description [Variation Report for NM_000304.4(PMP22):c.215C>G (p.Ser72Trp)]

NM_000304.4(PMP22):c.215C>G (p.Ser72Trp)

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.215C>G (p.Ser72Trp)
HGVS:
  • NC_000017.11:g.15239575G>C
  • NG_007949.1:g.30753C>G
  • NM_000304.4:c.215C>GMANE SELECT
  • NM_001281455.2:c.215C>G
  • NM_001281456.2:c.215C>G
  • NM_001330143.2:c.215C>G
  • NM_153321.3:c.215C>G
  • NM_153322.3:c.215C>G
  • NP_000295.1:p.Ser72Trp
  • NP_001268384.1:p.Ser72Trp
  • NP_001268385.1:p.Ser72Trp
  • NP_001317072.1:p.Ser72Trp
  • NP_696996.1:p.Ser72Trp
  • NP_696997.1:p.Ser72Trp
  • LRG_263t1:c.215C>G
  • LRG_263:g.30753C>G
  • NC_000017.10:g.15142892G>C
  • NM_000304.2:c.215C>G
  • NM_000304.3:c.215C>G
  • NR_104017.2:n.310C>G
  • NR_104018.2:n.210C>G
Protein change:
S72W
Links:
dbSNP: rs104894621
NCBI 1000 Genomes Browser:
rs104894621
Molecular consequence:
  • NM_000304.4:c.215C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281455.2:c.215C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281456.2:c.215C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330143.2:c.215C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153321.3:c.215C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_153322.3:c.215C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_104017.2:n.310C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_104018.2:n.210C>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000942186Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 15, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene.

Roa BB, Dyck PJ, Marks HG, Chance PF, Lupski JR.

Nat Genet. 1993 Nov;5(3):269-73.

PubMed [citation]
PMID:
8275092

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000942186.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces serine with tryptophan at codon 72 of the PMP22 protein (p.Ser72Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Dejerine–Sottas disease (PMID: 9055797). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Ser72 amino acid residue in PMP22 have been observed in affected individuals (PMID: 8275092, 9004143, 9585367, 10399754, 11314784). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 6, 2021

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