rs267607573

chr1-156134865-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_170707.4(LMNA):c.700C>T(p.Gln234Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156134865-C-T is Pathogenic according to our data. Variant chr1-156134865-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 48075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134865-C-T is described in Lovd as [Pathogenic]. Variant chr1-156134865-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.700C>T	p.Gln234Ter	stop_gained	4/12	ENST00000368300.9
LMNA	NM_005572.4	c.700C>T	p.Gln234Ter	stop_gained	4/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.700C>T	p.Gln234Ter	stop_gained	4/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.700C>T	p.Gln234Ter	stop_gained	4/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18585512, 31402444, 25525159, 21639948, 24846508, 27532257, 27576561, 24503780, 23582089) -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 15, 2022

This variant changes 1 nucleotide in exon 4 of the intermediate filament rod domain of the lamin A/C protein, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 18585512, 22337857, 23582089, 24503780, 27532257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LMNA function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 23, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln234*) in the LMNA gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in several individuals affected with autosomal-dominant LMNA-related disease (PMID: 18585512, 27532257, 24503780). ClinVar contains an entry for this variant (Variation ID: 48075). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2009

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2018

The p.Q234* pathogenic mutation (also known as c.700C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 700. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This variant has been reported in two unrelated patients with dilated cardiomyopathy, at least one of whom also exhibited cardiac conduction disease (Parks SB et al. Am. Heart J. 2008;156:161-9; Pugh TJ et al. Genet. Med. 2014;16:601-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.90
GERP RS		5.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0

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: rs267607573; hg19: chr1-156104656;