1-156134883-C-T

Position:

• chr1-156134883-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The ENST00000368300.9(LMNA):​c.718C>T​(p.Arg240Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,866 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.65

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000368300.9
• 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, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.718C>T	p.Arg240Trp	missense_variant	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.718C>T	p.Arg240Trp	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	c.718C>T	p.Arg240Trp	missense_variant	4/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.718C>T	p.Arg240Trp	missense_variant	4/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251442 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461866 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2023

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. 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: 279839). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is present in population databases (rs775964460, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 240 of the LMNA protein (p.Arg240Trp). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2021

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 279839; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 32041611) -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This missense variant replaces arginine with tryptophan at codon 240 of the LMNA 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 not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 2/251442 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

Jan 30, 2024

The p.R240W variant (also known as c.718C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 718. The arginine at codon 240 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Pathogenic	0.85
CardioboostCm	Uncertain	0.83
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;.;D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.2	M;.;M;M;M;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;.;.;D;.;.
Vest4		0.59
MutPred		0.58		Gain of catalytic residue at R240 (P = 0.0074);Gain of catalytic residue at R240 (P = 0.0074);Gain of catalytic residue at R240 (P = 0.0074);Gain of catalytic residue at R240 (P = 0.0074);Gain of catalytic residue at R240 (P = 0.0074);.;.;.;.;
MVP		0.78
MPC		1.9
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
Varity_R		0.68
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs775964460; hg19: chr1-156104674;