rs60872029

Positions:

• chr1-156115009-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_170707.4(LMNA):​c.94_96delAAG​(p.Lys32del) variant causes a conservative inframe deletion 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K32K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.34

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 13 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_170707.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-156115009-GAGA-G is Pathogenic according to our data. Variant chr1-156115009-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 66960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156115009-GAGA-G is described in Lovd as [Pathogenic]. Variant chr1-156115009-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.94_96delAAG	p.Lys32del	conservative_inframe_deletion	1/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.94_96delAAG	p.Lys32del	conservative_inframe_deletion	1/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.94_96delAAG	p.Lys32del	conservative_inframe_deletion	1/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.94_96delAAG	p.Lys32del	conservative_inframe_deletion	1/10		NM_005572.4	ENSP00000503633.1

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

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular dystrophy due to LMNA mutation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2024

This variant, c.94_96del, results in the deletion of 1 amino acid(s) of the LMNA protein (p.Lys32del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (EDMD), congenital muscular dystrophy, and inflammatory myopathy (PMID: 12467752, 15372542, 17377071, 18551513, 20980393, 21632249, 24806962, 26098624, 27600705). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66960). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LMNA function (PMID: 15372542, 21653823, 22090424, 23427149, 24806962). For these reasons, this variant has been classified as Pathogenic. -

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: rs60872029; hg19: chr1-156084800;