rs267607577

Positions:

• chr1-156136351-AGCACGCAC-A
• chr1-156136351-AGCACGCAC-AGCACGCACGCAC

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.1300_1307del​(p.Ala434Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• 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: 10.0

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 1-156136351-AGCACGCAC-A is Pathogenic according to our data. Variant chr1-156136351-AGCACGCAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179384.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.1300_1307del	p.Ala434Ter	frameshift_variant	7/10	ENST00000677389.1
LMNA	NM_170707.4	c.1300_1307del	p.Ala434Ter	frameshift_variant	7/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1300_1307del	p.Ala434Ter	frameshift_variant	7/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1300_1307del	p.Ala434Ter	frameshift_variant	7/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Nov 03, 2020

This variant has been observed in individual(s) with LMNA-related conditions (PMID: 27884249). ClinVar contains an entry for this variant (Variation ID: 179384). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala434*) 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). For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 08, 2013

The Ala434X variant in LMNA has not been reported in individuals with cardiomyop athy and data from large population studies are insufficient to assess the frequ ency of this variant in the general population. This variant introduces a deleti on of 8 bases and creates a premature termination codon at amino acid 434. This alteration is predicted to lead to a truncated or absent protein. Heterozygous l oss of function of the LMNA gene is an established disease mechanism for DCM. In summary, this variant is likely to be pathogenic, but additional studies are ne eded to fully establish its clinical significance. -

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: rs267607577; hg19: chr1-156106142;