NM_170707.4(LMNA):c.647G>A (p.Arg216His) AND Cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 13, 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:: RCV000778039.5

Allele description [Variation Report for NM_170707.4(LMNA):c.647G>A (p.Arg216His)]

NM_170707.4(LMNA):c.647G>A (p.Arg216His)

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.647G>A (p.Arg216His)

Other names:

p.R216H:CGT>CAT; p.Arg216His

HGVS:

NC_000001.11:g.156134812G>A
NG_008692.2:g.57240G>A
NM_001257374.3:c.311G>A
NM_001282624.2:c.404G>A
NM_001282625.2:c.647G>A
NM_001282626.2:c.647G>A
NM_005572.4:c.647G>A
NM_170707.4:c.647G>AMANE SELECT
NM_170708.4:c.647G>A
NP_001244303.1:p.Arg104His
NP_001269553.1:p.Arg135His
NP_001269554.1:p.Arg216His
NP_001269555.1:p.Arg216His
NP_005563.1:p.Arg216His
NP_005563.1:p.Arg216His
NP_733821.1:p.Arg216His
NP_733822.1:p.Arg216His
LRG_254t1:c.647G>A
LRG_254t2:c.647G>A
LRG_254:g.57240G>A
LRG_254p1:p.Arg216His
NC_000001.10:g.156104603G>A
NM_005572.3:c.647G>A
NM_170707.2:c.647G>A
NM_170707.3:c.647G>A

Protein change:

R104H

Links:

dbSNP: rs757041809

NCBI 1000 Genomes Browser:

rs757041809

Molecular consequence:

NM_001257374.3:c.311G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.647G>A - 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
SCV000914152	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34768595, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000914152

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 13, 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

Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants.

Ferradini V, Cosma J, Romeo F, De Masi C, Murdocca M, Spitalieri P, Mannucci S, Parlapiano G, Di Lorenzo F, Martino A, Fedele F, Calò L, Novelli G, Sangiuolo F, Mango R.

J Clin Med. 2021 Oct 29;10(21). doi: 10.3390/jcm10215075.

PubMed [citation]

PMID:: 34768595
PMCID:: PMC8584896

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 Color Diagnostics, LLC DBA Color Health, SCV000914152.4

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

Description

This missense variant replaces arginine with histidine at codon 216 of the lamin A/C protein. 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 an individual affected with dilated cardiomyopathy (PMID: 34768595). A different variant occurring at the same codon, p.Arg216Cys, is a well documented pathogenic mutation (Clinvar variation ID: 200938), indicating that arginine at this position is important for LMNA protein function. This variant has been identified in 7/282556 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 24, 2024

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