rs267607554

chr1-156135925-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.961C>T(p.Arg321Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,478 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 2.10

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 1-156135925-C-T is Pathogenic according to our data. Variant chr1-156135925-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 48096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135925-C-T is described in Lovd as [Pathogenic]. Variant chr1-156135925-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-156135925-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.961C>T	p.Arg321Ter	stop_gained	6/12	ENST00000368300.9
LMNA	NM_005572.4	c.961C>T	p.Arg321Ter	stop_gained	6/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.961C>T	p.Arg321Ter	stop_gained	6/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.961C>T	p.Arg321Ter	stop_gained	6/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461478 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727036

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000680 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2021	Not observed at significant frequency 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 with inappropriate localization into the endoplasmic reticulum affecting cellular homeostasis mechanisms (Carmosino et al., 2016); Reported in ClinVar (ClinVar Variant ID# 48096; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 29237675, 30609406, 16715312, 31977013, 17987279, 24001739, 24058181, 26899768, 27421120, 30319452, 24846508, 21840938, 30402260, 24503780, 29095976, 19875404, 31983221, 31447099, 31402444, 33019804, 30078822) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2017	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change creates a premature translational stop signal (p.Arg321*) 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 present in population databases (rs267607554, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and/or ventricular arrhythmia (PMID: 17987279, 19875404, 24001739, 24058181, 27421120, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48096). For these reasons, this variant has been classified as Pathogenic. -

Primary familial dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 31, 2022

Variant summary: LMNA c.961C>T (p.Arg321X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant has been shown to induce incomplete nonsense mediated decay resulting in nearly absent/reduced expression of the truncated protein (Al-Saaidi_2013, Carmosino_2016). Truncations downstream of this position have been classified as pathogenic in ClinVar (e.g. c.1057C>T [p.Gln353Ter]; c.1228C>T [p.Gln410Ter]). The variant was absent in 249364 control chromosomes (gnomAD). c.961C>T has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy (Zeller_2006, Al-Saaidi_2013, Carmosino_2016, Hayashi_2020). These data indicate that the variant is very likely to be associated with disease. Functional evaluation of the protein has shown that the truncated protein is lowly expressed and accumulated within the ER, causing ER stress via the unfolded protein response. This in turn caused abnormal Ca2+ handling via the ER, resulting in a reduced Ca2+ release rate (~25%) compared with wildtype LMNA (Carmosino_2016). The variant is shown to also increase apoptosis by 45% (Carmosino_2016). Six ClinVar submitters have assessed the variant since 2014: all six have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 03, 2015

The p.Arg321X variant has been reported in at least 5 individuals with DCM, and segregated with disease in at least 3 affected relatives (Zeller 2006, Geiger 20 08, M?ller 2009, Sylvius 2011, Al-Saaidi 2013, Hasselberg 2014). In addition, th is variant has been identified by our laboratory in at least 9 affected members of one family with DCM, including one affected obligate carrier (LMM unpublished data) and has also been reported by other clinical laboratories in ClinVar (Var iation ID 48096). Additionally, the p.Arg312X variant has been identified in 1/8 38 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org/; dbSNP rs267607554). This variant leads to a premature termi nation codon at position 321, which is predicted to result in a truncated or abs ent protein. In vitro studies show that little to no LMNA protein is present in fibroblasts from patients carrying this variant (Geiger 2008, Al-Saaidi 2013). I n summary, this variant meets criteria to be classified as pathogenic for DCM in an autosomal dominant manner based upon presence in multiple affected individua ls, segregation studies, absence from the general population and functional stud ies. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PS3_Moderate (Ric hards 2015). -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2023

The c.961C>T (p.R321*) alteration, located in exon 6 (coding exon 6) of the LMNA gene, consists of a C to T substitution at nucleotide position 961. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 321. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in unrelated individuals with dilated cardiomyopathy (DCM) with conduction system disease and ventricular arrhythmias, and has been reported to segregate with disease in families (Geiger, 2008; Møller, 2009; Hasselberg, 2014; C. Seidman pers comm; Cuenca, 2016; Walsh, 2017). This variant was also detected in an individual with DCM with features suggesting skeletal muscle involvement (Sylvius, 2011). Functional studies report the mRNA produced by this variant is largely subject to nonsense mediated decay (NMD), while studies also report a skewed ratio of lamin A and lamin C protein which may disrupt lamin polymer stability, and incomplete NMD which may result in dominant negative effect from truncated protein retained in the endoplasmic reticulum, contributing to disease (Geiger, 2008; Al-Saaidi, 2013; Carmosino, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.96
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs267607554; hg19: chr1-156105716; COSMIC: COSV61543148; COSMIC: COSV61543148;