rs58978449

chr1-156134942-TAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_170707.4(LMNA):c.781_783del(p.Lys261del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.22

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_170707.4
• PM4: Nonframeshift variant in NON repetitive region in NM_170707.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-156134942-TAAG-T is Pathogenic according to our data. Variant chr1-156134942-TAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134942-TAAG-T is described in Lovd as [Pathogenic]. Variant chr1-156134942-TAAG-T is described in Lovd as [Likely_pathogenic]. Variant chr1-156134942-TAAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_005572.4	c.781_783del	p.Lys261del	inframe_deletion	4/10	ENST00000677389.1
LMNA	NM_170707.4	c.781_783del	p.Lys261del	inframe_deletion	4/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.781_783del	p.Lys261del	inframe_deletion	4/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.781_783del	p.Lys261del	inframe_deletion	4/10		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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	The c.781_783delAAG pathogenic variant has been reported in multiple individuals with autosomal dominant Emery Dreifuss muscular dytrophy, including as a de novo change (Bonne et al., 2000, Rudenskaya et al., 2008, Rankin et al., 2006). The c.781_783delAAG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.781_783delAAG variant results in an in-frame deletion of a single Lysine residue, denoted p.Lys261del. This varaint occurs at a position that is conserved across species. Therefore, based on the currently available information, we interpret c.781_783delAAG as a pathogenic variant, and its presence is consistent with an LMNA-related disorder in this individual. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2017	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 11, 2023

ClinVar contains an entry for this variant (Variation ID: 48080). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects LMNA function (PMID: 22068161). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individuals with autosomal dominant LMNA-related conditions (PMID: 10908904, 10939567, 11503164, 22068161). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.781_783del, results in the deletion of 1 amino acid(s) of the LMNA protein (p.Lys261del), but otherwise preserves the integrity of the reading frame. -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2011

The Lys261del variant has been reported in 2 individuals with a clinical diagnos is and family history of Emery-Dreifuss muscular dystrophy. The variant was abse nt from over 680 control chromosomes, supporting a pathogenic role (Bonne 2000, Brown 2001, Felice 2000). In addition, our laboratory has detected this variant in one individual whose clinical features were consistent with those of the prev iously published patients, further increasing the likelihood that this variant i s pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.781_783delAAG variant (also known as p.K261del) is located in coding exon 4 of the LMNA gene. This variant results from an in-frame AAG deletion at nucleotide positions 781 to 783. This results in the in-frame deletion of a lysine at codon 261. This alteration has been reported in subjects with LMNA-associated disease and has been reported as de novo (Felice KJ et al. Neurology, 2000 Jul;55:275-80; Bonne G et al. Ann Neurol, 2000 Aug;48:170-80; Brown CA et al. Am J Med Genet, 2001 Sep;102:359-67; Ben Yaou R et al. Brain Commun, 2021 Jul;3:fcab075). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs58978449; hg19: chr1-156104733;