rs58048078

Positions:

• chr1-156134942-T-A
• chr1-156134942-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_170707.4(LMNA):​c.777T>A​(p.Tyr259*) variant causes a stop gained change involving the alteration of a non-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 (★). Synonymous variant affecting the same amino acid position (i.e. Y259Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4 O:1
• Conservation: PhyloP100: 1.35

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 12 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 1-156134942-T-A is Pathogenic according to our data. Variant chr1-156134942-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14511.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156134942-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.777T>A	p.Tyr259*	stop_gained	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.777T>A	p.Tyr259*	stop_gained	4/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.777T>A	p.Tyr259*	stop_gained	4/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.777T>A	p.Tyr259*	stop_gained	4/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:3 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2017	The Y259X variant in the LMNA gene has been reported in association with limb gridle muscular dystrophy and cardiomyopathy (Muchir et al., 2003; van Tintelen et al., 2007; van Spaendonck-Zwarts et al., 2013). Y259X was first reported in the homozygous state in a newborn who died at birth and in the heterozygous state in his maternal grandmother who had a diagnosis of limb girdle muscular dystrophy and bradycardia (Muchir et al., 2003) Y259X was subsequently identified in a female with a first-degree AV block and supraventricular tachycardias who was found to be related to the family reported by Muchir et al. (van Tintelen et al., 2007). Of 10 patients from this family, 5 carried pacemakers, however, a diagnosis of DCM was not mentioned in any of the patients (van Tintelen et al., 2007). Nevertheless, Y259X has been reported in one individual with DCM with possible neuromuscular involvement (van Spaendonck-Zwarts et al., 2013).Functional studies in fibroblast cells showed a reduction in lamin A and C expression when Y259X was in the heterozygous state and a complete absence of expression in the homozygous state (Muchir et al., 2003). A truncated protein product was not observed in any of the fibroblast cells harboring the Y259X variant suggesting haploinsufficiency is the likely disease mechanism (Muchir et al., 2003). In another study, Y259X in the homozygous state was shown to cause nuclear rupture and loss of cellular compartmentalization (De Vos et al., 2011). Additionally, other nonsense variants in the LMNA gene have been reported in HGMD in association with DCM (Stenson P et al., 2014). Furthermore, the Y259X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, Y259X is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 25, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.87
GERP RS		1.0

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: rs58048078; hg19: chr1-156104733;