rs863225024

Positions:

• chr1-156138749-C-CG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_170707.4(LMNA):​c.1961dup​(p.Thr655AsnfsTer49) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 4.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156138749-C-CG is Pathogenic according to our data. Variant chr1-156138749-C-CG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66878.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1961dup	p.Thr655AsnfsTer49	frameshift_variant	11/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1961dup	p.Thr655AsnfsTer49	frameshift_variant	11/12	1	NM_170707.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 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 AF: 0.00000137 AC: 2 AN: 1461170 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

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

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial partial lipodystrophy, Dunnigan type Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 10, 2023	PS3, PS4, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2013	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2022	Reported in association with dilated cardiomyopathy, though clinical details were not provided (Haas et al., 2015); Reported as a founder mutation in Creole individuals from Reunion Island, and described to have a dose-dependent effect with more severe clinical manifestations in homozygous individuals compared to heterozygous individuals; non-penetrance in heterozygous individuals has been observed (Le Dour et al., 2011; Andre et al., 2015); Cultured fibroblasts from individuals heterozygous and homozygous this this variant showed misshapen nuclei, and fibroblasts homozygous for the variant demonstrated increased oxidative stress and features of premature senescence (Le Dour et al., 2011); Frameshift variant predicted to result in replacement of the last 10 amino acids with 48 different amino acids; Not observed in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 66878; ClinVar); This variant is associated with the following publications: (PMID: 25819867, 25163546, 21346069, 17711925, 10939567, 35528128, 34292171) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

This sequence change results in a frameshift in the LMNA gene (p.Thr655Asnfs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the LMNA protein and extend the protein by 38 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with familial partial lipodystrophy (FPLD2) and dilated cardiomyopathy (PMID: 17711925, 25163546, 25819867). This variant is also known as c.1870_1871insG (p.R624fs). ClinVar contains an entry for this variant (Variation ID: 66878). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1961dupG pathogenic mutation, located in coding exon 11 of the LMNA gene, results from a duplication of G at nucleotide position 1961, causing a translational frameshift with a predicted alternate stop codon (p.T655Nfs*49). This mutation has been identified in multiple homozygous individuals with familial partial lipodystrophy type 2 (FPLD2) (Decaudain A et al. J. Clin. Endocrinol. Metab., 2007 Dec;92:4835-44; Le Dour C et al. J. Clin. Endocrinol. Metab., 2011 May;96:E856-62; Andre P et al. Am. Heart J., 2015 Apr;169:587-93). In one study, 7/10 homozygous and 3/25 heterozygous individuals demonstrated cardiolaminopathy manifestations (Andre P et al. Am. Heart J., 2015 Apr;169:587-93). This mutation was also identified in a cohort of individuals with dilated cardiomyopathy (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a). Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of LMNA, is not expected to trigger nonsense-mediated mRNA decay, impacts the last 10 amino acids, and results in the elongation of the protein by 38 amino acids. The exact functional impact of the added amino acids is unknown at this time; however, the resulting protein from patient fibroblasts showed no evidence of posttranslational farnesylation CSIM site (Le Dour C et al. J. Clin. Endocrinol. Metab., 2011 May;96:E856-62). 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. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This variant inserts 1 nucleotide in exon 11 of the lamin A transcript (NM_170707.3), causing a frameshift in the last exon and addition of 49 new amino acids before introducing a stop codon. This variant represents a single nucleotide insertion in the 3' untranslated region of the lamin C transcript (NM_005572.3: c.*986dup). This results in a protein product that is 39 amino acids longer than the normal protein product. A functional study has shown that this variant causes abnormal post-translational maturation and premature senescence (PMID: 21346069). This variant has been reported as a founder variant from Reunion Island in association with lipodystrophy and laminopathy, showing a more severe phenotype in homozygous individuals than in heterozygous individuals (PMID: 17711925, 21346069, 25819867, 34292171). This variant has been reported in the heterozygous state in an individual affected with dilated cardiomyopathy (PMID: 25163546) and in the homozygous state in several individuals affected with dilated cardiomyopathy (PMID: 34292171). It has also been reported in an individual affected with sudden cardiac arrest (PMID: 35528128); the variant was also identified in 3 unaffected family members. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863225024; hg19: chr1-156108540;