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NM_170707.4(LMNA):c.496C>T (p.Arg166Trp) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 19, 2023
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:
RCV000695871.5

Allele description [Variation Report for NM_170707.4(LMNA):c.496C>T (p.Arg166Trp)]

NM_170707.4(LMNA):c.496C>T (p.Arg166Trp)

Genes:
LOC126805877:MED14-independent group 3 enhancer GRCh37_chr1:156099693-156100892 [Gene]
LMNA:lamin A/C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_170707.4(LMNA):c.496C>T (p.Arg166Trp)
HGVS:
  • NC_000001.11:g.156130756C>T
  • NG_008692.2:g.53184C>T
  • NM_001257374.3:c.160C>T
  • NM_001282624.2:c.253C>T
  • NM_001282625.2:c.496C>T
  • NM_001282626.2:c.496C>T
  • NM_005572.4:c.496C>T
  • NM_170707.4:c.496C>TMANE SELECT
  • NM_170708.4:c.496C>T
  • NP_001244303.1:p.Arg54Trp
  • NP_001269553.1:p.Arg85Trp
  • NP_001269554.1:p.Arg166Trp
  • NP_001269555.1:p.Arg166Trp
  • NP_005563.1:p.Arg166Trp
  • NP_733821.1:p.Arg166Trp
  • NP_733822.1:p.Arg166Trp
  • LRG_254t2:c.496C>T
  • LRG_254:g.53184C>T
  • NC_000001.10:g.156100547C>T
  • NM_170707.2:c.496C>T
  • NM_170707.3:c.496C>T
  • NM_170707.4:c.496C>T
Protein change:
R166W
Links:
dbSNP: rs370200334
NCBI 1000 Genomes Browser:
rs370200334
Molecular consequence:
  • NM_001257374.3:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.253C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth disease type 2
Synonyms:
Charcot-Marie-Tooth, Type 2
Identifiers:
MONDO: MONDO:0018993; MedGen: C0270914

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000824395Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 19, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy.

Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A, Li D, Jakobs P, Litt M, Porter CB, Rahko PS, Hershberger RE.

Am Heart J. 2008 Jul;156(1):161-9. doi: 10.1016/j.ahj.2008.01.026. Epub 2008 Mar 12.

PubMed [citation]
PMID:
18585512
PMCID:
PMC2527054

Lamin A/C gene mutations in familial cardiomyopathy with advanced atrioventricular block and arrhythmia.

Saga A, Karibe A, Otomo J, Iwabuchi K, Takahashi T, Kanno H, Kikuchi J, Keitoku M, Shinozaki T, Shimokawa H.

Tohoku J Exp Med. 2009 Aug;218(4):309-16.

PubMed [citation]
PMID:
19638735
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824395.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 166 of the LMNA protein (p.Arg166Trp). This variant is present in population databases (rs370200334, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 574040). 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 LMNA protein function with a positive predictive value of 95%. This variant disrupts the p.Arg166 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18585512, 19638735, 26084686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024