rs397517915

Variant names:

• chr1-156135921-GC-G
• rs397517915
• NM_170707.4:c.958delC

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.958delC​(p.Leu320PhefsTer160) 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
• Conservation: PhyloP100: 3.27

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 1-156135921-GC-G is Pathogenic according to our data. Variant chr1-156135921-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 48095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135921-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.958delC	p.Leu320PhefsTer160	frameshift_variant	Exon 6 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.958delC	p.Leu320PhefsTer160	frameshift_variant	Exon 6 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.958delC	p.Leu320PhefsTer160	frameshift_variant	Exon 6 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.958delC	p.Leu320PhefsTer160	frameshift_variant	Exon 6 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Jan 14, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu320Phefs*160) in the LMNA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257). ClinVar contains an entry for this variant (Variation ID: 48095). Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 11, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Frameshift 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; Many other downstream frameshift variants in the LMNA gene have been reported in HGMD in association with DCM (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27532257, 24503780, 22464770, 24846508, 31383942, 31402444) -

Primary dilated cardiomyopathy Pathogenic:1

Feb 27, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Leu320fs variant in LMNA is predicted to alter the protein?s amino acid sequ ence beginning at position 320 and lead to a premature termination codon 160 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This variant has been detected in 1 individual tested by our la boratory and was absent from 380 race matched control chromosomes (Lakdawala 201 2). A different variant leading to a nearly identical amino acid change (c.959de lT; Arg321fsX159) has been reported in 5 affected individuals in one family with variable expression of DCM, arrhythmia and muscular dystrophy (Brodsky 2000). C onsidering this second family, the Leu320fs variant meets our criteria to be cla ssified as pathogenic (http://pcpgm.partners.org/LMM). -

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: rs397517915; hg19: chr1-156105712;