rs60580541

Positions:

• chr1-156137210-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The ENST00000368300.9(LMNA):​c.1586C>T​(p.Ala529Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A529T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:1
• Conservation: PhyloP100: 2.22

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000368300.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156137209-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2065107.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38659558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1586C>T	p.Ala529Val	missense_variant	9/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1586C>T	p.Ala529Val	missense_variant	9/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1586C>T	p.Ala529Val	missense_variant	9/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.1586C>T	p.Ala529Val	missense_variant	9/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mandibuloacral dysplasia with type A lipodystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2005

- -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Jun 21, 2023

- -

Familial partial lipodystrophy, Dunnigan type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 18, 2021

The heterozygous c.1586C>T (p.Ala529Val) variant identified in the LMNA gene substitutes a very well conserved Alanine for Valine at amino acid529/664 (exon 9/12). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score: 1.0328) and Benign (REVEL; score: 0.492) to the function of the canonical transcript. This variant is reported in ClinVar as Pathogenic (VarID:14513) and has been reported at the homozygous state in 4 affected individual (3 families) in the literature with mandibuloacral dysplasia (MAD) [PMID: 15998779, 27100822]. Heterozygous carriers have been reported without phenotypic abnormalities of MAD but two of them had diabetes mellitus. Hyperglycemia in heterozygous carriers might be related to the heterozygous p.Ala529Val variant in the LMNA gene, but these data have to be confirmed. Given the lack of compelling evidence for its pathogenicity in metabaloic disorders, the c.1586C>T, p.Ala529Val variant identified in the LMNA gene is reported as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Dec 21, 2021

The p.A529V pathogenic mutation (also known as c.1586C>T), located in coding exon 9 of the LMNA gene, results from a C to T substitution at nucleotide position 1586. The alanine at codon 529 is replaced by valine, an amino acid with similar properties. This variant has been reported in homozygous individuals with autosomal recessive mandibuloacral dysplasia (MAD); heterozygous carrier family members were reported to be unaffected with MAD or other laminopathy-related phenotypes (Cogulu O et al. Am J Med Genet A, 2003 Jun;119A:391-2; Garg A et al. J Clin Endocrinol Metab, 2005 Sep;90:5259-64; Ozer L et al. Clin Dysmorphol, 2016 Jul;25:91-7). This variant is 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. Based on the supporting evidence, this variant is expected to be causative of mandibuloacral dysplasia (MAD) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathy-related phenotypes is unclear. -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
CardioboostCm	Benign	0.0061
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Uncertain	0.64	.;.;.;D;.;.;.;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.77	T;D;T;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.43	N;.;N;N;N;.;.;.;.
MutationTaster	Benign	0.59	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.43	N;.;N;N;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	1.0	T;.;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.017	B;.;B;B;.;.;B;.;.
Vest4		0.73
MutPred		0.61		Loss of stability (P = 0.0476);.;Loss of stability (P = 0.0476);Loss of stability (P = 0.0476);Loss of stability (P = 0.0476);.;.;.;.;
MVP		0.99
MPC		0.36
ClinPred		0.26	T
GERP RS		5.6
Varity_R		0.36
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs60580541; hg19: chr1-156107001;