rs1553261855

Positions:

• chr1-156114968-G-GCT

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.52_53dup​(p.Thr19ProfsTer78) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S17S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.0150

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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 773 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156114968-G-GCT is Pathogenic according to our data. Variant chr1-156114968-G-GCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 543212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_005572.4	c.52_53dup	p.Thr19ProfsTer78	frameshift_variant	1/10	ENST00000677389.1
LMNA	NM_170707.4	c.52_53dup	p.Thr19ProfsTer78	frameshift_variant	1/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.52_53dup	p.Thr19ProfsTer78	frameshift_variant	1/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.52_53dup	p.Thr19ProfsTer78	frameshift_variant	1/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

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

Invitae

Apr 28, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 543212). This variant is also known as c.50_51insCT, Ser17fs. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr19Profs*78) 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). -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 31, 2023

The c.52_53dup (p.Thr19Profs*78) variant of the LMNA gene is located on the exon 1 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Thr19Profs*78), resulting in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with dilated cardiomyopathy (PMID: 11138304, 12854972, 12920062). The variant is reported in ClinVar (ID: 543212). This variant is absent in the general population database (gnomAD). Therefore, the c.52_53dup (p.Thr19Profs*78) variant of LMNA has been classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553261855; hg19: chr1-156084759;