rs794728597

Positions:

• chr1-156130623-CAAG-C

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.367_369del​(p.Lys123del) variant causes a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.28

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 region_of_interest Coil 1B (size 137) in uniprot entity LMNA_HUMAN there are 60 pathogenic changes around while only 0 benign (100%) 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 1-156130623-CAAG-C is Pathogenic according to our data. Variant chr1-156130623-CAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_005572.4	c.367_369del	p.Lys123del	inframe_deletion	2/10	ENST00000677389.1	NP_005563.1
LMNA	NM_170707.4	c.367_369del	p.Lys123del	inframe_deletion	2/12	ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.367_369del	p.Lys123del	inframe_deletion	2/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.367_369del	p.Lys123del	inframe_deletion	2/10		NM_005572.4	ENSP00000503633

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: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 200947). This variant has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 22019351, 24642510; Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This variant, c.367_369del, results in the deletion of 1 amino acid(s) of the LMNA protein (p.Lys123del), but otherwise preserves the integrity of the reading frame. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2018

The c.367_369delAAG likely pathogenic variant in the LMNA gene has been reported previously in association with cardiomyopathy and laminopathy (Keller et al., 2012; Kajino et al., 2014). Keller et al. reported c.367_369delAAG in a 43-year-old woman with severe arrhythmia and a three generation family history of sudden death, cardiomyopathy, and arrhythmia. This variant was inherited from her affected father and was shown to segregate with disease in an affected sibling (Keller et al., 2012). The c.367_369delAAG variant has also been shown to segregate with disease in one relative tested at GeneDx. Kajino et al. reported an additional individual with the c.367_369delAAG variant who was initially diagnosed with childhood fiber type dysplasia (CTFD). The c.367_369delAAG variant has also been reported as a likely pathogenic variant by an outside laboratory in ClinVar (SCV000264016.1; Landrum et al., 2016). The c.367_369delAAG variant results in an in-frame deletion of a Lysine at position 123 of the LMNA gene and is located in the alpha-helical rod domain. Lastly, this variant is not observed in large population cohorts (Lek et al., 2016). -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 04, 2015

- -

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: rs794728597; hg19: chr1-156100414;