NM_170707.4(LMNA):c.496C>T (p.Arg166Trp) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 17, 2018
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:: RCV002334317.2

Allele description [Variation Report for NM_170707.4(LMNA):c.496C>T (p.Arg166Trp)]

NM_170707.4(LMNA):c.496C>T (p.Arg166Trp)

Genes:

LOC126805877:MED14-independent group 3 enhancer GRCh37_chr1:156099693-156100892 [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.496C>T (p.Arg166Trp)

HGVS:

NC_000001.11:g.156130756C>T
NG_008692.2:g.53184C>T
NM_001257374.3:c.160C>T
NM_001282624.2:c.253C>T
NM_001282625.2:c.496C>T
NM_001282626.2:c.496C>T
NM_005572.4:c.496C>T
NM_170707.4:c.496C>TMANE SELECT
NM_170708.4:c.496C>T
NP_001244303.1:p.Arg54Trp
NP_001269553.1:p.Arg85Trp
NP_001269554.1:p.Arg166Trp
NP_001269555.1:p.Arg166Trp
NP_005563.1:p.Arg166Trp
NP_733821.1:p.Arg166Trp
NP_733822.1:p.Arg166Trp
LRG_254t2:c.496C>T
LRG_254:g.53184C>T
NC_000001.10:g.156100547C>T
NM_170707.2:c.496C>T
NM_170707.3:c.496C>T
NM_170707.4:c.496C>T

Protein change:

R166W

Links:

dbSNP: rs370200334

NCBI 1000 Genomes Browser:

rs370200334

Molecular consequence:

NM_001257374.3:c.160C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.253C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.496C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002643451	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 17, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28663758, 28679633 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002643451

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 17, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes.

Florwick A, Dharmaraj T, Jurgens J, Valle D, Wilson KL.

Front Genet. 2017;8:79. doi: 10.3389/fgene.2017.00079.

PubMed [citation]

PMID:: 28663758
PMCID:: PMC5471320

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

Details of each submission

From Ambry Genetics, SCV002643451.2

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

Description

The p.R166W variant (also known as c.496C>T), located in coding exon 2 of the LMNA gene, results from a C to T substitution at nucleotide position 496. The arginine at codon 166 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in an exome cohort, but clinical details were not provided (Florwick A et al. Front Genet. 2017;8:79). In the same study, structural modeling suggested that this variant may impact lamin dimerization; however, experimental evidence is not currently available (Florwick A et al. Front Genet, 2017;8:79). A likely pathogenic alteration, p.R166P, has been described in the same codon (Parks SB et al. Am Heart J. 2008;156(1):161-9). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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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