1-156130709-C-T

Position:

• chr1-156130709-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The ENST00000368300.9(LMNA):​c.449C>T​(p.Thr150Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T150A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.91

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 9 ACMG points.

• PM1: In a hotspot region, there are 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156130708-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.449C>T	p.Thr150Ile	missense_variant	2/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.449C>T	p.Thr150Ile	missense_variant	2/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.449C>T	p.Thr150Ile	missense_variant	2/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.449C>T	p.Thr150Ile	missense_variant	2/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 16, 2023

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 09, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr150Ile variant in LMNA has been previously reported in 1 individual with DCM (Hirtle-L ewis 2013) and was absent from large population studies. In addition, another di sease-causing variant at this position (p.Thr150Pro) has been reported in 2 indi viduals with Emery-Dreifuss muscular dystrophy with conduction system disease (F elice 2000, Schamer 2011) and was identified by our laboratory in 4 family membe rs with clinical features of LMNA-related cardiomyopathy (DCM, muscle weakness, and/or conduction system disease; LMM unpublished data), suggesting that a chang e at this position may not be tolerated. Computational prediction tools and cons ervation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, whi le there is some suspicion for a pathogenic role, the clinical significance of t he p.Thr150Ile variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2023

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; Reported in individuals with dilated cardiomyopathy (Hirtle-Lewis et al., 2013; Chami et al., 2014); This variant is associated with the following publications: (PMID: 24037902, 1300868, 30402260, 25448463, 10939567, 20848652, 10908904) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2024

The p.T150I variant (also known as c.449C>T), located in coding exon 2 of the LMNA gene, results from a C to T substitution at nucleotide position 449. The threonine at codon 150 is replaced by isoleucine, an amino acid with similar properties. This variant has been detected in individuals from dilated cardiomyopathy cohorts (Hirtle-Lewis M et al. Clin Cardiol, 2013 Oct;36:628-33; Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61; Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). Another alteration at the same codon, p.T150P (c.448A>C), has been reported in association with phenotypes consistent with laminopathies (Felice KJ. Neurology. 2000 Jul;55(2):275-80). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	4.0	H;.;H;H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.069	T;T;T;T;T;T;T;D;T
Polyphen		0.93	P;.;D;P;.;.;D;.;.
Vest4		0.84
MutPred		0.51		Loss of phosphorylation at T150 (P = 0.0398);Loss of phosphorylation at T150 (P = 0.0398);Loss of phosphorylation at T150 (P = 0.0398);Loss of phosphorylation at T150 (P = 0.0398);Loss of phosphorylation at T150 (P = 0.0398);.;.;.;.;
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.90

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

Other links and lift over

dbSNP: rs869069617; hg19: chr1-156100500;