rs267607646

Variant names:

• chr1-156115265-T-TG
• rs267607646
• NM_170707.4:c.348dupG

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.348dupG​(p.Lys117GlufsTer10) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.421

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 1-156115265-T-TG is Pathogenic according to our data. Variant chr1-156115265-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 48061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.348dupG	p.Lys117GlufsTer10	frameshift_variant	Exon 1 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.348dupG	p.Lys117GlufsTer10	frameshift_variant	Exon 1 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.348dupG	p.Lys117GlufsTer10	frameshift_variant	Exon 1 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.348dupG	p.Lys117GlufsTer10	frameshift_variant	Exon 1 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Aug 22, 2012

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Charcot-Marie-Tooth disease type 2 Pathogenic:1

May 09, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). This variant has been reported to segregate with LMNA-related disease in a family and has been reported in an individual affected with dilated cardiomyopathy (PMID: 19328042, 22464770). This variant is also known as 0348_349insG, K117fs in the literature. ClinVar contains an entry for this variant (Variation ID: 48061). This sequence change creates a premature translational stop signal (p.Lys117Glufs*10) in the LMNA gene. It is expected to result in an absent or disrupted protein product. -

Primary dilated cardiomyopathy Pathogenic:1

Feb 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys117GlufsX10 variant has been previously reported in 1 Chinese family with DCM, AV block, and atrial fibrillation (Pan 2009). The variant segregated with disease in 12 affected individuals (including 5 obligate carriers; Pan 2009). It has also been reported in ClinVar (Variation ID 48061), but was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 117 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In vitro functional studies support that the p.Lys117GlufsX10 variant leads to reduced mRNA and protein levels (Pan 2009). Loss of function of the LMNA gene is an established disease mechanism in autosomal dominant DCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DCM. ACMG/AMP criteria applied: PVS1, PP1_Strong, PM2, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

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: rs267607646; hg19: chr1-156085056;