Variant rs777841827 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.3511331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.1879C>T	p.Arg627Cys	missense_variant	11/12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.1879C>T	p.Arg627Cys	missense_variant	11/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

3

AN:

152246

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000322

AC:

8

AN:

248608

Hom.:

0

AF XY:

0.0000296

AC XY:

4

AN XY:

135018

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000536

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

61

AN:

1461334

Hom.:

0

Cov.:

32

AF XY:

0.0000385

AC XY:

28

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

3

AN:

152246

Hom.:

0

Cov.:

32

AF XY:

0.0000134

AC XY:

1

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

0

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 15, 2024	PM2 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 25, 2021

Variant summary: LMNA c.1879C>T (p.Arg627Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 248646 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1879C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy and Primary Electrical Disease as well as in one carrier (Houben_2012, Hazebroek_2015, Proost_2017, Hoorntje_2017, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (van Tienen_2018). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 16, 2023

This missense variant replaces arginine with cysteine at codon 627 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that there were no nuclear envelope or morphology abnormalities in fibroblasts of carrier individuals (PMID: 28790152, 30420677). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 22918509, 30847666). One of these individuals also carried a pathogenic variant in the RBM20 gene that could explain the observed phenotype (PMID: 30847666). This variant has been reported in an individual affected with cardiac arrhythmia (PMID: 27884249), in an individual affected with primary electrical disease (PMID: 28341588), in an individual affected with unspecified cardiomyopathy (PMID: 28790152), and in an individual affected with sudden infant death (PMID: 37589201). This variant has also been reported in an individual with left ventricular dysfunction (PMID: 29540472); this individual also carried a different pathogenic variant in the LMNA gene that could explain the observed phenotype. This variant has been identified in 8/248608 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. -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 627 of the LMNA protein (p.Arg627Cys). This variant is present in population databases (rs777841827, gnomAD 0.006%). This missense change has been observed in individual(s) with cardiac arrhythmias, dilated cardiomyopathy, and/or unspecified cardiomyopathy (PMID: 22918509, 27884249, 28341588, 29540472, 30847666). ClinVar contains an entry for this variant (Variation ID: 543199). Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 28790152, 30420677). 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. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces arginine with cysteine at codon 627 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that there were no nuclear envelope or morphology abnormalities in fibroblasts of carrier individuals (PMID: 28790152, 30420677). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 22918509, 30847666). One of these individuals also carried a pathogenic variant in the RBM20 gene that could explain the observed phenotype (PMID: 30847666). This variant has been reported in an individual affected with cardiac arrhythmia (PMID: 27884249), in an individual affected with primary electrical disease (PMID: 28341588), in an individual affected with unspecified cardiomyopathy (PMID: 28790152), and in an individual affected with sudden infant death (PMID: 37589201). This variant has also been reported in an individual with left ventricular dysfunction (PMID: 29540472); this individual also carried a different pathogenic variant in the LMNA gene that could explain the observed phenotype. This variant has been identified in 8/248608 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The p.R627C variant (also known as c.1879C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1879. The arginine at codon 627 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in an individual with dilated cardiomyopathy (who carried a second LMNA alteration p.R331Q (c.992G>A)) and in two individuals with primary electrical disease (Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10; Proost D et al. J Mol Diagn, 2017 May;19:445-459; Kumar S et al. J. Am. Coll. Cardiol., 2016 Nov;68:2299-2307). In addition, functional studies used immunofluorescence on cultured fibroblasts to show that this alteration did not cause any nuclear envelope abnormalities (Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10; Houben F et al. Histochem. Cell Biol., 2013 Jan;139:119-34). This amino acid position is well conserved in 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

CardioboostCm

Benign

0.0048

BayesDel_addAF

Pathogenic

0.31

D

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

28

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

.;D;.;.;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

D

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Uncertain

0.19

D

MetaRNN

Benign

0.35

T;T;T;T;T

MetaSVM

Uncertain

0.54

D

MutationAssessor

Benign

1.8

.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.71

T

PROVEAN

Benign

-0.38

N;N;N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.039

D;D;D;D;D

Sift4G

Benign

0.11

T;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.80

MutPred

0.29

.;Loss of MoRF binding (P = 0.0064);.;.;.;

MVP

0.96

MPC

1.1

ClinPred

0.30

T

GERP RS

4.7

Varity_R

0.14

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs777841827

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over