rs267607634

chr1-156136045-G-Achr1-156136045-G-C

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.1081G>A(p.Glu361Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E361Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.77

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr1-156136045-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245948.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 1-156136045-G-A is Pathogenic according to our data. Variant chr1-156136045-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136045-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1081G>A	p.Glu361Lys	missense_variant	6/12	ENST00000368300.9
LMNA	NM_005572.4	c.1081G>A	p.Glu361Lys	missense_variant	6/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1081G>A	p.Glu361Lys	missense_variant	6/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1081G>A	p.Glu361Lys	missense_variant	6/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727222

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

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Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 16218190). 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: 66772). This missense change has been observed in individual(s) with clinical features of autosomal dominant Emery-Dreifuss muscular dystrophy (PMID: 20848652; Invitae). 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 361 of the LMNA protein (p.Glu361Lys). -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.5	H;.;H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D
Polyphen		0.38	B;.;P;P;.;.;P;.
Vest4		0.93
MutPred		0.67		Gain of ubiquitination at E361 (P = 0.0109);Gain of ubiquitination at E361 (P = 0.0109);Gain of ubiquitination at E361 (P = 0.0109);Gain of ubiquitination at E361 (P = 0.0109);Gain of ubiquitination at E361 (P = 0.0109);.;.;.;
MVP		0.93
MPC		1.7
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.66
gMVP		0.95

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: rs267607634; hg19: chr1-156105836;