rs397517906

Positions:

chr1-156134890-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_170707.4(LMNA):c.725C>T(p.Ala242Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 4.93

Variant links:

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

LMNA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

PP5

Variant 1-156134890-C-T is Pathogenic according to our data. Variant chr1-156134890-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48076.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Uncertain_significance=1, Pathogenic=1}. Variant chr1-156134890-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.725C>T	p.Ala242Val	missense_variant	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4 linkuse as main transcript	c.725C>T	p.Ala242Val	missense_variant	4/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.725C>T	p.Ala242Val	missense_variant	4/12	1	NM_170707.4	ENSP00000357283	P1	P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.725C>T	p.Ala242Val	missense_variant	4/10		NM_005572.4	ENSP00000503633		P02545-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251432

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2023	Identified in patients with cardiomyopathy and arrhythmia in published literature (van Lint et al., 2019; Murdock et al., 2021); Identified in a family with arrhythmogenic cardiomyopathy with right venctricular heart failure (RVHF) and arrhythmias in published literature (Chen et al., 2022); the p.(A242V) variant was also identified in the proband's nephew who had an abnormal ECG but was absent in a sister with arrhythmogenic cardiomyopathy without RVHF. This family harbored several additional cardiogenetic variants.; Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 30765282, 30402260, 30847666, 28679633, 34363016, 35526016, 10939567) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 03, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 27, 2014

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 48076). This missense change has been observed in individuals with arrhythmogenic cardiomyopathy (PMID: 30765282, 30847666, 35526016). This variant is present in population databases (rs397517906, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the LMNA protein (p.Ala242Val). -

Primary familial dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 28, 2020

Variant summary: LMNA c.725C>T (p.Ala242Val) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. One study reports that cardiac patients with an LMNA mutation located upstream of the NLS (nuclear localization signal, amino acids 417-422) have a more adverse cardiac phenotype, and some missense mutations can be as harmful as non-missense ones (Captur_2018). The variant allele was found at a frequency of 8e-06 in 251432 control chromosomes. c.725C>T has been reported in the literature in one individual affected with Arrhythmogenic right ventricular cardiomyopathy (ARVC, Vischer_2019) and individuals affected with Dilated Cardiomyopathy (van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely pathogenic (4x). According to one of these laboratories, this variant was identified in 3 Caucasian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affected relatives from 2 families (including 3 obligate carriers). At our laboratory, two sibs tested testing positive for this variant have no clinical phenotype, however they were well below the age of onset at only ages 8 and 10 years old. Additional family history was reportedly positive for DCM in their father and paternal aunt. However, no genetic testing records available on them. These data indicate that the variant is very likely to be associated with disease. Based on the evidence outlined above, until additional clinical reports supported by functional studies are identified, the variant is classified as likely pathogenic. -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 03, 2016

The p.Ala242Val variant in LMNA has been identified by our laboratory in 3 Cauca sian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affecte d relatives from 2 families (including 3 obligate carriers). This variant has be en identified in 1/66618 of European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517906). Although alanine (Ala) at position 242 is not well conserved in evolution, computational predict ion tools suggest that it may impact the protein. However, this information is n ot predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala242 Val variant is likely pathogenic. -

Dilated cardiomyopathy 1A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Dec 17, 2019

This c.725C>T (p.Ala242Val) variant in the LMNA gene has been reported in multiple unrelated individuals, including one case with ARVC (PMID: 30765282), 4 cases of arrhythmia (PMID: 30847666). The clinical diagnostic lab LMM reported 3 Caucasian adults (1 with ARVC, 1 with clinical features of ARVC, and 1 with DCM) and segregated with disease (DCM, unspecified cardiomyopathy, CHF, SCD) in 6 affected relatives from 2 families (ClinVar Accession# SCV000065054.5). The c.725C>T variant is rare in the general population and has been reported twice in gnomAD. Furthermore, computational tools suggest the Alanine 242 is conserved and the change of p.Ala242Val is predicted to be deleterious. Therefore, the c.725C>T (p. Ala242Val) variant in the LMNA gene is classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The p.A242V variant (also known as c.725C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 725. The alanine at codon 242 is replaced by valine, an amino acid with similar properties. Testing at another laboratory has shown this alteration in multiple affected individuals with cardiomyopathy and/or arrhythmia and also demonstrated segregation with disease across two families (personal communication). In addition, this variant was reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) heart failure cohort; however, the affected individual also had a PKP2 variant detected (Vischer AS et al. Int. J. Cardiol., 2019 07;286:99-103). This variant has also been detected in individuals from a genetic testing cohort who were reported to have arrhythmia, unknown cardiomyopathy, dilated cardiomyopathy, or non-ischemic cardiomyopathy; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Murdock DR et al. Genet Med, 2021 12;23(12):2404-2414). This variant was detected in an additional family reported to have ARVC, arrhythmia and heart failure in which variants in other cardiac-related genes were also detected (Chen J et al. Orphanet J Rare Dis. 2022 May;17(1):183). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Charcot-Marie-Tooth disease type 2B1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

Aug 21, 2024

No available literature for CMT phenotype. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

CardioboostCm

Uncertain

0.30

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;.;.;D;.;.;.;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;T;D;D;D;D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.7

H;.;H;H;H;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0080

D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.076

T;D;D;D;D;D;D;T;D

Polyphen

0.95

P;.;P;D;.;.;D;.;.

Vest4

0.63

MutPred

0.56

Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);Gain of MoRF binding (P = 0.2284);.;.;.;.;

MVP

0.90

MPC

1.9

ClinPred

0.94

GERP RS

5.5

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.0

Varity_R

0.36

gMVP

0.95

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.

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