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NM_170707.4(LMNA):c.1158G>C (p.Arg386Ser) AND Charcot-Marie-Tooth disease type 2

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 26, 2022
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:
RCV002518430.2

Allele description [Variation Report for NM_170707.4(LMNA):c.1158G>C (p.Arg386Ser)]

NM_170707.4(LMNA):c.1158G>C (p.Arg386Ser)

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.1158G>C (p.Arg386Ser)
HGVS:
  • NC_000001.11:g.156136214G>C
  • NG_008692.2:g.58642G>C
  • NM_001257374.3:c.822G>C
  • NM_001282624.2:c.915G>C
  • NM_001282625.2:c.1158G>C
  • NM_001282626.2:c.1158G>C
  • NM_005572.4:c.1158G>C
  • NM_170707.4:c.1158G>CMANE SELECT
  • NM_170708.4:c.1158G>C
  • NP_001244303.1:p.Arg274Ser
  • NP_001269553.1:p.Arg305Ser
  • NP_001269554.1:p.Arg386Ser
  • NP_001269555.1:p.Arg386Ser
  • NP_005563.1:p.Arg386Ser
  • NP_733821.1:p.Arg386Ser
  • NP_733822.1:p.Arg386Ser
  • LRG_254t2:c.1158G>C
  • LRG_254:g.58642G>C
  • NC_000001.10:g.156106005G>C
  • NM_170707.2:c.1158G>C
Protein change:
R274S
Links:
dbSNP: rs879253933
NCBI 1000 Genomes Browser:
rs879253933
Molecular consequence:
  • NM_001257374.3:c.822G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.915G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.1158G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.1158G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.1158G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.1158G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.1158G>C - 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

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003333438Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Mar 26, 2022) 		germlineclinical testing

PubMed (2)
[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

Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling.

Zwerger M, Jaalouk DE, Lombardi ML, Isermann P, Mauermann M, Dialynas G, Herrmann H, Wallrath LL, Lammerding J.

Hum Mol Genet. 2013 Jun 15;22(12):2335-49. doi: 10.1093/hmg/ddt079. Epub 2013 Feb 19.

PubMed [citation]
PMID:
23427149
PMCID:
PMC3658163

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, SCV003333438.2

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

Description

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 386 of the LMNA protein (p.Arg386Ser). 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 variant disrupts the p.Arg386 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23427149; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 245758). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency).

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

Last Updated: Feb 20, 2024