1-156137204-G-T

Position:

• chr1-156137204-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_170707.4(LMNA):​c.1580G>T​(p.Arg527Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,446,064 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R527C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.39

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]

LMNA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 9 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 chr1-156137204-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 1-156137204-G-T is Pathogenic according to our data. Variant chr1-156137204-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 919926.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1580G>T	p.Arg527Leu	missense_variant	9/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1580G>T	p.Arg527Leu	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.1580G>T	p.Arg527Leu	missense_variant	9/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1580G>T	p.Arg527Leu	missense_variant	9/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446064 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718404

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: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg527 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18796515, 19432833, 23497705, 25286833, 25982065). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 919926). This missense change has been observed in individuals with autosomal recessive mandibuloacral dysplasia type A and progeria (PMID: 22549407). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 527 of the LMNA protein (p.Arg527Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 19, 2020

This missense variant replaces arginine with leucine at codon 527 of the LMNA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in homozygosity in three individuals (aged 4-10) from two Egyptian families affected with mandibuloacral dysplasia (PMID: 22549407). The probands’ mothers (aged 30 and 38) were heterozygous carriers and clinically unaffected. An ultrastructural study of the skin in the mothers has shown that some fibroblasts showed irregularities and invaginations of the nuclear membrane and were surrounded by the disrupted bundles of collagen fibers (PMID: 23775434). However, clinical relevance of this observation is not known. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 14, 2024

This missense variant replaces arginine with leucine at codon 527 of the LMNA protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with dilated cardiomyopathy. This variant has been reported in homozygosity in three individuals (aged 4-10) from two Egyptian families affected with mandibuloacral dysplasia (PMID: 22549407). In both families, the unaffected parents were heterozygous carriers. An ultrastructural study of the skin in one parent has shown that some fibroblasts showed irregularities and invaginations of the nuclear membrane and were surrounded by the disrupted bundles of collagen fibers (PMID: 23775434). However, clinical relevance of this observation is not known. This variant has also been reported in homozygosity in two unrelated individuals (aged 2-5) from two Egyptian families affected with a laminopathy with progeroid features phenotype (PMID: 34680903). In both families, the unaffected parents were heterozygous carriers. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to be associated with autosomal recessive mandibuloacral dysplasia and laminopathy (ClinVar variation ID: 919926). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
CardioboostCm	Benign	0.039
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;.;.;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.8	L;.;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.038	D;.;D;D;D;D;D;D;D
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;D
Polyphen		0.49	P;.;B;P;.;.;P;.;.
Vest4		0.79
MutPred		0.62		Loss of catalytic residue at R527 (P = 0.0304);.;Loss of catalytic residue at R527 (P = 0.0304);Loss of catalytic residue at R527 (P = 0.0304);Loss of catalytic residue at R527 (P = 0.0304);.;.;.;.;
MVP		0.99
MPC		0.46
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.82

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: rs57520892; hg19: chr1-156106995;