NM_170707.4(LMNA):c.1381G>T (p.Asp461Tyr) AND Charcot-Marie-Tooth disease type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 26, 2021
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:: RCV001060202.6

Allele description [Variation Report for NM_170707.4(LMNA):c.1381G>T (p.Asp461Tyr)]

NM_170707.4(LMNA):c.1381G>T (p.Asp461Tyr)

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.1381G>T (p.Asp461Tyr)

HGVS:

NC_000001.11:g.156136921G>T
NG_008692.2:g.59349G>T
NM_001257374.3:c.1045G>T
NM_001282624.2:c.1138G>T
NM_001282625.2:c.1381G>T
NM_001282626.2:c.1381G>T
NM_005572.4:c.1381G>T
NM_170707.4:c.1381G>TMANE SELECT
NM_170708.4:c.1381G>T
NP_001244303.1:p.Asp349Tyr
NP_001269553.1:p.Asp380Tyr
NP_001269554.1:p.Asp461Tyr
NP_001269555.1:p.Asp461Tyr
NP_005563.1:p.Asp461Tyr
NP_733821.1:p.Asp461Tyr
NP_733822.1:p.Asp461Tyr
LRG_254t1:c.1381G>T
LRG_254t2:c.1381G>T
LRG_254:g.59349G>T
NC_000001.10:g.156106712G>T
NM_005572.3:c.1381G>T
NM_170707.2:c.1381G>T
NM_170707.3:c.1381G>T
P02545:p.Asp461Tyr

Protein change:

D349Y

Links:

UniProtKB: P02545#VAR_064973; dbSNP: rs267607642

NCBI 1000 Genomes Browser:

rs267607642

Molecular consequence:

NM_001257374.3:c.1045G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.1138G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1381G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1381G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001224878	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 26, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28679633, 20848652, 23328570, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001224878

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 26, 2021)

germline

clinical testing

PubMed (4)
[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

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.

Ito K, Patel PN, Gorham JM, McDonough B, DePalma SR, Adler EE, Lam L, MacRae CA, Mohiuddin SM, Fatkin D, Seidman CE, Seidman JG.

Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7689-7694. doi: 10.1073/pnas.1707741114. Epub 2017 Jul 5.

PubMed [citation]

PMID:: 28679633
PMCID:: PMC5528995

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.

Scharner J, Brown CA, Bower M, Iannaccone ST, Khatri IA, Escolar D, Gordon E, Felice K, Crowe CA, Grosmann C, Meriggioli MN, Asamoah A, Gordon O, Gnocchi VF, Ellis JA, Mendell JR, Zammit PS.

Hum Mutat. 2011 Feb;32(2):152-67. doi: 10.1002/humu.21361. Epub 2011 Jan 25.

PubMed [citation]

PMID:: 20848652

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001224878.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28679633). 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: 66819). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or Emery-Dreifuss muscular dystrophy (PMID: 20848652, 23328570). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 461 of the LMNA protein (p.Asp461Tyr).

#	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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