NM_170707.4(LMNA):c.136A>G (p.Ile46Val) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 4, 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:: RCV001230439.8

Allele description [Variation Report for NM_170707.4(LMNA):c.136A>G (p.Ile46Val)]

NM_170707.4(LMNA):c.136A>G (p.Ile46Val)

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.136A>G (p.Ile46Val)

HGVS:

NC_000001.11:g.156115054A>G
NG_008692.2:g.37482A>G
NM_001282625.2:c.136A>G
NM_001282626.2:c.136A>G
NM_005572.4:c.136A>G
NM_170707.4:c.136A>GMANE SELECT
NM_170708.4:c.136A>G
NP_001269554.1:p.Ile46Val
NP_001269555.1:p.Ile46Val
NP_005563.1:p.Ile46Val
NP_733821.1:p.Ile46Val
NP_733822.1:p.Ile46Val
LRG_254t2:c.136A>G
LRG_254:g.37482A>G
NC_000001.10:g.156084845A>G
NM_170707.2:c.136A>G
NM_170707.3:c.136A>G

Protein change:

I46V

Links:

dbSNP: rs267607615

NCBI 1000 Genomes Browser:

rs267607615

Molecular consequence:

NM_001282625.2:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.136A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.136A>G - 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

Recent activity

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kin of IRRE-like protein 2 [Perognathus longimembris pacificus]
kin of IRRE-like protein 2 [Perognathus longimembris pacificus]
gi|2240590585|ref|XP_048225423.1|

Protein
GTP pyrophosphokinase family protein [Brachybacterium saurashtrense]
GTP pyrophosphokinase family protein [Brachybacterium saurashtrense]
gi|1442784896|gnl|PRJNA483375|DWV08 0|gb|AXK45444.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001402918	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16891232, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001402918

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 4, 2022)

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

Primary myocardial dysfunction in autosomal dominant EDMD. A tissue doppler and cardiovascular magnetic resonance study.

Smith GC, Kinali M, Prasad SK, Bonne G, Muntoni F, Pennell DJ, Nihoyannopoulos P.

J Cardiovasc Magn Reson. 2006;8(5):723-30.

PubMed [citation]

PMID:: 16891232

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001402918.5

#	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 valine, which is neutral and non-polar, at codon 46 of the LMNA protein (p.Ile46Val). 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. 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: 66815). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 16891232; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

#	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: Sep 29, 2024

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