NM_170707.4(LMNA):c.1201C>T (p.Arg401Cys) AND Cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000769728.7

Allele description [Variation Report for NM_170707.4(LMNA):c.1201C>T (p.Arg401Cys)]

NM_170707.4(LMNA):c.1201C>T (p.Arg401Cys)

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.1201C>T (p.Arg401Cys)

HGVS:

NC_000001.11:g.156136257C>T
NG_008692.2:g.58685C>T
NM_001257374.3:c.865C>T
NM_001282624.2:c.958C>T
NM_001282625.2:c.1201C>T
NM_001282626.2:c.1201C>T
NM_005572.4:c.1201C>T
NM_170707.4:c.1201C>TMANE SELECT
NM_170708.4:c.1201C>T
NP_001244303.1:p.Arg289Cys
NP_001269553.1:p.Arg320Cys
NP_001269554.1:p.Arg401Cys
NP_001269555.1:p.Arg401Cys
NP_005563.1:p.Arg401Cys
NP_005563.1:p.Arg401Cys
NP_733821.1:p.Arg401Cys
NP_733822.1:p.Arg401Cys
LRG_254t1:c.1201C>T
LRG_254t2:c.1201C>T
LRG_254:g.58685C>T
LRG_254p1:p.Arg401Cys
NC_000001.10:g.156106048C>T
NM_005572.3:c.1201C>T
NM_170707.2:c.1201C>T
NM_170707.3:c.1201C>T
P02545:p.Arg401Cys
c.1201C>T

Protein change:

R289C

Links:

UniProtKB: P02545#VAR_072818; dbSNP: rs61094188

NCBI 1000 Genomes Browser:

rs61094188

Molecular consequence:

NM_001257374.3:c.865C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.958C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000901149	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001355731	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 15, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12376891, 23977161, 24623722, 25448463, 32698523, 32793522, 32880476, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000901149

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 30, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001355731

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 15, 2023)

germline

clinical testing

PubMed (8)
[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

[Hauptmann-Thannhauser muscular dystrophy and differential diagnosis of myopathies associated with contractures].

Hanisch F, Neudecker S, Wehnert M, Zierz S.

Nervenarzt. 2002 Oct;73(10):1004-11. German.

PubMed [citation]

PMID:: 12376891

Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.

Yang L, Munck M, Swaminathan K, Kapinos LE, Noegel AA, Neumann S.

PLoS One. 2013;8(8):e71850. doi: 10.1371/journal.pone.0071850.

PubMed [citation]

PMID:: 23977161
PMCID:: PMC3748058

See all PubMed Citations (8)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000901149.1

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

#	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

From Color Diagnostics, LLC DBA Color Health, SCV001355731.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces arginine with cysteine at codon 401 of the lamin A/C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is located in the C-terminal region of the protein that mediates interaction with many protein binding partners. Functional studies have shown that for the most part, this variant does not adversely affect protein interaction, although interaction with some binding partners may be affected (PMID: 23977161, 24623722, 32698523). This variant has been reported in an individual affected with Hauptmann-Thannhauser muscular dystrophy (PMID: 12376891), in a family and an unrelated individual affected with dilated cardiomyopathy (PMID: 25448463, 32880476), and in another individual affected with congenital heart defects (PMID: 32793522). This variant has also been identified in 22/280520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Nov 10, 2024

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