NM_170707.4(LMNA):c.686T>C (p.Ile229Thr) AND Primary dilated cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 11, 2024
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:: RCV003998328.2

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]

Observations:

Condition(s)

Name:: Primary dilated cardiomyopathy (DCM)
Synonyms:: Dilated Cardiomyopathy
Identifiers:: EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004845037	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32846814, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004845037

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

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	3	not provided	not provided	108544	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004845037.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces isoleucine with threonine at codon 229 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with dilated cardiomyopathy (Fang 2018, dissertation, University of Electronic Science and Technology of China). This variant has also been reported in five individuals affected with cardiac conduction disease and has been shown to segregate with disease in this family (PMID: 32846814). This variant has not been identified 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	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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