rs1553261891

chr1-156115012-A-Gchr1-156115012-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):c.94A>G(p.Lys32Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K32T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.32

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 17 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156115013-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2503449.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 1-156115012-A-G is Pathogenic according to our data. Variant chr1-156115012-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 476837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156115012-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.94A>G	p.Lys32Glu	missense_variant	1/12	ENST00000368300.9
LMNA	NM_005572.4	c.94A>G	p.Lys32Glu	missense_variant	1/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.94A>G	p.Lys32Glu	missense_variant	1/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.94A>G	p.Lys32Glu	missense_variant	1/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 15, 2022

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 476837). This missense change has been observed in individual(s) with autosomal dominant LMNA-related neuromuscular conditions (PMID: 28688748, 32571898; Clinvar). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 32 of the LMNA protein (p.Lys32Glu). -

Congenital muscular dystrophy due to LMNA mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jun 15, 2018

The heterozygous p.Lys32Glu variant was identified by our study in one individual with congenital muscular dystrophy. Trio exome analysis showed this variant to be de novo. This variant has been identified in the literature in one affected heterozygous proband (Monges et al. 2011). This variant was absent from large population studies. The Lysine (Lys) at position 32 is highly conserved in mammals and evolutionarily distant species, supporting that a change at this position may not be tolerated. Additionally, computational prediction tools suggest that this variant may impact the protein. A lab has reported this variant as likely pathogenic in Clinvar; however, the phenotype listed is Charcot-Marie-Tooth disease. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic for congenital muscular dystrophy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;T;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.86
MutPred		0.63		Loss of ubiquitination at K32 (P = 0.0067);Loss of ubiquitination at K32 (P = 0.0067);Loss of ubiquitination at K32 (P = 0.0067);Loss of ubiquitination at K32 (P = 0.0067);Loss of ubiquitination at K32 (P = 0.0067);
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1
Varity_R		0.93
gMVP		1.0

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: rs1553261891; hg19: chr1-156084803;