NM_170707.4(LMNA):c.686T>C (p.Ile229Thr) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 27, 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:: RCV000538272.6

Allele description [Variation Report for NM_170707.4(LMNA):c.686T>C (p.Ile229Thr)]

NM_170707.4(LMNA):c.686T>C (p.Ile229Thr)

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.686T>C (p.Ile229Thr)

HGVS:

NC_000001.11:g.156134851T>C
NG_008692.2:g.57279T>C
NM_001257374.3:c.350T>C
NM_001282624.2:c.443T>C
NM_001282625.2:c.686T>C
NM_001282626.2:c.686T>C
NM_005572.4:c.686T>C
NM_170707.4:c.686T>CMANE SELECT
NM_170708.4:c.686T>C
NP_001244303.1:p.Ile117Thr
NP_001269553.1:p.Ile148Thr
NP_001269554.1:p.Ile229Thr
NP_001269555.1:p.Ile229Thr
NP_005563.1:p.Ile229Thr
NP_733821.1:p.Ile229Thr
NP_733822.1:p.Ile229Thr
LRG_254t2:c.686T>C
LRG_254:g.57279T>C
NC_000001.10:g.156104642T>C
NM_170707.2:c.686T>C
NM_170707.3:c.686T>C

Protein change:

I117T

Links:

dbSNP: rs727505357

NCBI 1000 Genomes Browser:

rs727505357

Molecular consequence:

NM_001257374.3:c.350T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.686T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.686T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.686T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.686T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.686T>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000657819	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32846814, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000657819

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 27, 2023)

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

Next-generation sequencing identifies a novel heterozygous I229T mutation on LMNA associated with familial cardiac conduction disease.

Gao Y, Han Z, Wu X, Lan R, Zhang X, Shen W, Liu Y, Liu X, Lan X, Xu B, Xu W.

Medicine (Baltimore). 2020 Aug 21;99(34):e21797. doi: 10.1097/MD.0000000000021797.

PubMed [citation]

PMID:: 32846814
PMCID:: PMC7447464

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, SCV000657819.4

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 229 of the LMNA protein (p.Ile229Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 32846814; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180115). 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. For these reasons, this variant has been classified as Pathogenic.

#	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: May 7, 2024

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