rs60682848

Positions:

• chr1-156134838-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.673C>T​(p.Arg225Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000657 in 152,212 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMNA NM_170707.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 6.11

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 1-156134838-C-T is Pathogenic according to our data. Variant chr1-156134838-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 48074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134838-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.673C>T	p.Arg225Ter	stop_gained	4/12	ENST00000368300.9
LMNA	NM_005572.4	c.673C>T	p.Arg225Ter	stop_gained	4/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.673C>T	p.Arg225Ter	stop_gained	4/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.673C>T	p.Arg225Ter	stop_gained	4/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000882 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 08, 2019	PVS1, PS4, PM2, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2021	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; Published functional studies demonstrate a damaging effect as this variant results in accelerated nuclear senescence and apoptosis of cardiomyocytes (Siu et al., 2012); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 48074; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11561226, 18035086, 25525159, 19638735, 23631840, 24237251, 27054045, 23362510, 24503780, 19882644, 27532257, 28573431, 28600387, 31395619, 31668660, 31427369, 28754655, 31309180, 30934932, 30078822, 32793522, 31383942, 32160020, 31402444) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Dilated cardiomyopathy 1A Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Apr 27, 2023	PVS1, PS3, PS4, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University	Apr 27, 2021	- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 19, 2019

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

This sequence change creates a premature translational stop signal (p.Arg225*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with LMNA-related conditions (PMID: 11561226, 22806367, 23362510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48074). For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 16, 2011

The Arg225X variant in LMNA leads to a premature stop at codon 225, which is pre dicted to lead to a truncated or absent protein. This variant has been reported in 4 individuals with variable clinical features that included DCM, conduction s ystem disease, and musculoskeletal abnormalities (Jakobs 2001, Van Tintelen 2007 , Saga 2009, Carboni 2010). These presentations are typical manifestations of pa thogenic LMNA variants. In addition, this variant segregated with disease in at least 7 affected family members and was absent from at least 600 control chromo somes (Jakobs 2001, Van Tintelen 2007, Saga 2009, Carboni 2010). In summary, the Arg225X variant meets our criteria for pathogenicity based on the severity of t he change, segregation in affected individuals, and absence from controls. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The p.R225* pathogenic mutation (also known as c.673C>T), located in coding exon 4 of the LMNA gene, results from a C to T substitution at nucleotide position 673. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in numerous individuals with LMNA-related phenotypes, including dilated cardiomyopathy, cardiac conduction disease, and musculoskeletal abnormalities (van Tintelen JP et al. Am. Heart J. 2007;154:1130-9; Saga A et al. Tohoku J. Exp. Med. 2009;218:309-16; Laksman Z et al. Clin. Genet. 2014;86:580-4; Mellor G et al. Circ Cardiovasc Genet. 2017;10(3): e001686; Nishiuchi S et al. Circ Cardiovasc Genet. 2017;10(6):e001603; Walsh R et al. Genet. Med. 2017;19:192-203). Moreover, this alteration segregated with disease in multiple large families (Jakobs PM et al. J. Card. Fail. 2001;7:249-56; Carboni N et al. Muscle Nerve. 2012;46:187-92; Siu CW et al. Aging (Albany NY). 2012;4:803-822; Arimura T et al. Cardiovasc. Res. 2013;99:382-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 09, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.90
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8

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: rs60682848; hg19: chr1-156104629; COSMIC: COSV61543425; COSMIC: COSV61543425;