rs757041809

chr1-156134812-G-Achr1-156134812-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_170707.4(LMNA):c.647G>A(p.Arg216His) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,614,060 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. R216C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9
• Conservation: PhyloP100: 6.89

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 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, 12 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 chr1-156134811-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200938.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=3, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.647G>A	p.Arg216His	missense_variant	4/12	ENST00000368300.9
LMNA	NM_005572.4	c.647G>A	p.Arg216His	missense_variant	4/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.647G>A	p.Arg216His	missense_variant	4/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.647G>A	p.Arg216His	missense_variant	4/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251176 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44 AN XY: 727238

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: 0.0000558

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2022	Reported in at least one patient with DCM with abnormal nuclei in approximately 15% of cultured fibroblasts (Van Tienen et al., 2019; Verdonschot et al., 2020); also reported in one patient with Charcot-Marie-Tooth (Volodarsky et al., 2021); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32880476, 30420677, 32376792) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -

Primary dilated cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2024	The p.Arg216His variant in LMNA has been reported in 2 heterozygous individuals with DCM and 1 individual who also carried a second LMNA variant of uncertain significance (Ferradini 2021 PMID: 34768595, Horvat 2019 PMID: 29892087, van Tienen 2019 PMID: 30420677), as well as 1 individual with ventricular tachycardia (Kumar 2016 PMID: 27506821). It has also been identified in 0.0164% (1/6084) of Middle Eastern chromosomes and 0.005424% (64/1180036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 200964). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg216Cys) has been identified in individuals with DCM and is classified as likely pathogenic by this laboratory. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP3, PM5_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces arginine with histidine at codon 216 of the lamin A/C 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 34768595). A different variant occurring at the same codon, p.Arg216Cys, is a well documented pathogenic mutation (Clinvar variation ID: 200938), indicating that arginine at this position is important for LMNA protein function. This variant has been identified in 7/282556 chromosomes 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. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 216 of the LMNA protein (p.Arg216His). This variant is present in population databases (rs757041809, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 30420677, 32376792, 32880476, 34495297). ClinVar contains an entry for this variant (Variation ID: 200964). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg216 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23183350, 27506821, 28878402, 29237675, 29943882, 30007954). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Dilated cardiomyopathy 1A Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University

Apr 27, 2021

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 13, 2022

This missense variant replaces arginine with histidine at codon 216 of the lamin A/C 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 34768595). A different variant occurring at the same codon, p.Arg216Cys, is a well documented pathogenic mutation (Clinvar variation ID: 200938), indicating that arginine at this position is important for LMNA protein function. This variant has been identified in 7/282556 chromosomes 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. -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 08, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The p.R216H variant (also known as c.647G>A), located in coding exon 4 of the LMNA gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts, as well as a Charcot-Marie-Tooth cohort; however, clinical details were limited in these cases (Horvat C et al. Genet Med, 2019 01;21:133-143; van Tienen FHJ et al. Eur J Hum Genet, 2019 03;27:389-399; Ferradini V et al. J Clin Med, 2021 Oct;10:[ePub ahead of print]; Volodarsky M et al. J Med Genet, 2021 04;58:284-288). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
CardioboostCm	Benign	0.069
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.7	M;.;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D
Polyphen		0.94	P;.;P;P;.;.;P;.;.
Vest4		0.67
MutPred		0.61		Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);.;.;.;.;
MVP		0.92
MPC		1.7
ClinPred		0.89	D
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.50
gMVP		0.88

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: rs757041809; hg19: chr1-156104603;