rs794728593

Positions:

• chr1-156134933-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.768G>A​(p.Val256=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMNA NM_170707.4 synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.28

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-156134933-G-A is Pathogenic according to our data. Variant chr1-156134933-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.768G>A	p.Val256=	synonymous_variant	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.768G>A	p.Val256=	synonymous_variant	4/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.768G>A	p.Val256=	synonymous_variant	4/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.768G>A	p.Val256=	synonymous_variant	4/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 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: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change affects codon 256 of the LMNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LMNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 15 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy with conduction disease (PMID: 28679633). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200941). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 28679633). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2024

Published functional studies demonstrate premature splicing of exon 4 which deleted the terminal 45 base pairs and resulted in the loss of 15 aa in the rod domain of LMNA (PMID: 28679633); In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34076677, 28679633) -

Dilated cardiomyopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 16, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2. -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 14, 2017

The p.Val256Val variant in LMNA has been identified in 1 family with DCM and sud den death and segregated with disease in >35 affected relatives (Ito 2017). Sequ encing of RNA from individuals carrying the variant showed that this variant cau ses premature splicing of exon 4, resulting in a terminal deletion of 45 bps and loss of the last 15 amino acids of the exon (Ito 2017). This variant has not be en identified in large population studies. In summary, this variant meets criter ia to be classified as pathogenic for DCM in an autosomal dominant manner based upon its functional impact and segregation in affected individuals. ACMG/AMP Cri teria applied: PS3; PP1_Strong; PM2; PP3 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.768G>A pathogenic mutation (also known as p.V256V), located in coding exon 4, results from a G to A substitution at nucleotide position 768 of the LMNA gene. This nucleotide substitution does not change the amino acid at codon 256. This alteration has been reported in a multi-generation family with dilated cardiomyopathy (DCM) and conduction system disease, where strong disease segregation was identified (Lynch HT et al. JAMA, 1973 Sep;225:1465-70; Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jul;114:7689-7694). This mutation was also reported in affected individuals from an additional family with a history of DCM and sudden cardiac death (Duong et al., J Biol Methods, 2017 Sept;4(3):e78). In addition, an aberrant transcript that lacks the last 45bp of exon 4 was identified in patients from the original family, as well as in mini-gene assays (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 Jul;114:7689-7694). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Benign	0.70
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.90		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728593; hg19: chr1-156104724;