rs267607618

Positions:

• chr1-156136350-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.1294C>T​(p.Gln432*) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

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

LMNA (HGNC:):

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 1-156136350-C-T is Pathogenic according to our data. Variant chr1-156136350-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136350-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1294C>T	p.Gln432*	stop_gained	7/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1294C>T	p.Gln432*	stop_gained	7/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1294C>T	p.Gln432*	stop_gained	7/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1294C>T	p.Gln432*	stop_gained	7/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2016	The Q432X pathogenic variant in the LMNA gene has been reported in two family members with idiopathic dilated cardiomyopathy as well as two unaffected relatives (Moller et al., 2009). Q432X was absent in 700 control alleles in this study and was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations (Moller et al., 2009). Q432X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the LMNA gene have been reported in HGMD in association with cardiomyopathy and laminopathy (Stenson P et al., 2014). In vitro studies have shown that Q432X proteins form aggregates, sequester LINC (Linker of Nucleoskeleton and Cytoskeleton) complex components and cause chromosomal and transcription factor rearrangements (Yang et al., 2013). However, it is unclear to what extent these changes play a role in the formation of idiopathic DCM (Yang et al., 2013). -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 05, 2017	p.Gln432* (c.1294C>T) in the LMNA gene (NM_170707.3) Given the type of variation, the rarity, and the case data, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). However, we recommend segregation testing on the affected relatives to help confirm pathogenicity. There are additional entries in ClinVar suggesting there is likely additional (unpublished) case data. This variant was identified in 1 Caucasian idiopathic dilated cardiomyopathy patient and was subsequently found in 3 family members of this patient (Moller et al 2009 PMID 19875404). See table below for family pedigree. Note that the variant was identified in 2 “affected” and 2 “unaffected” individuals. The affecteds has LMNA typical phenotypes with DCM, heart failure, LBBB, atrial fibrillation, NSVT, AV block. The “unaffecteds” are a 43-year-old with hypertension since young adulthood and incomplete RBBB/LVH, and a 9-year-old. This was a study of 172 unrelated Caucasian idiopathic dilated cardiomyopathy patients who had LMNA and 11 other DCM genes sequenced. While this specific nonsense variant has only been seen in one other case, there is sufficient data supporting nonsense variants in LMNA in general as disease-causing. There are at least 11 different nonsense variants reported in LMNA associated with the various laminopathy phenotypes, including primarily dilated cardiomyopathy, conduction system disease, or muscular dystrophy (LGMD, EDMD) (Cowan J et al 2011, http://www.dmd.nl/lmna_seqvar.html, Dittmer et al 2011). Many frameshift variants have also been reported. We have seen another LMNA nonsense variant in a family with a familial cardiomyopathy consistent with the typical laminopathy phenotype. I reviewed the data on several other reported LMNA nonsense variants, which support this class of variants as disease causing. For example, Geiger et al (2007) report a nonsense variant (R321X) in a family with DCM and sudden death; three affected family members were genotyped and they all had the variant. mRNA and protein studies on patient skin fibroblasts and LV myocardium were consistent with mRNA mediated nonsense decay. Yang et al (2013) studied this variant in vitro and found that this variant disrupts the “linker of nucleoskeleton and cytoskeleton” complex and causes chromosomal and transcription factor rearrangements. The variant has not been seen in ~64,350 individuals not selected for cardiomyopathy. There is no variation at codon 432 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 1/24/16). Controls were 185 anonymous newborn blood spots plus 165 healthy blood donors; total of 350 controls, 700 alleles. The variant was absent in controls. -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2023

This sequence change creates a premature translational stop signal (p.Gln432*) in the LMNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 66800). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 19875404). This variant is not present in population databases (gnomAD no frequency). -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2015

The p.Gln432X in LMNA has been previously reported in 1 adult with DCM and condu ction system disease as well as in 1 affected relative (M?ller 2009). This varia nt was absent from large population studies. It leads to a premature termination codon at position 432, and in-vitro functional studies have shown that this var iant results in a truncated protein with abnormal function and localization (Yan g 2013). Truncating LMNA variants are well reported individuals with DCM and/or conduction system disease. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln432X variant is likely pa thogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2019

The p.Q432* pathogenic mutation (also known as c.1294C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1294. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This mutation has been reported in individuals with dilated cardiomyopathy (DCM) and appears to segregate with disease in affected family members (Møller DV et al. Eur. J. Heart Fail., 2009 Nov;11:1031-5; Nishiuchi S et al. Circ Cardiovasc Genet, 2017 Dec;10:[Epub ahead of print]). Functional studies showed changes in protein localization and the formation of aggregates, although the functional impact of these findings in not clear (Yang L et al. PLoS ONE, 2013 Aug;8:e71850). 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	0.59
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.96
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs267607618; hg19: chr1-156106141;