1-156136951-C-G

Variant names:

• chr1-156136951-C-G
• rs28928902
• NM_170707.4:c.1411C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_170707.4(LMNA):​c.1411C>G​(p.Arg471Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 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. R471P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 0.752

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 12 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 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 chr1-156136951-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.991
• PP5: Variant 1-156136951-C-G is Pathogenic according to our data. Variant chr1-156136951-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66824.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, not_provided=1}. Variant chr1-156136951-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1411C>G	p.Arg471Gly	missense_variant	Exon 8 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1411C>G	p.Arg471Gly	missense_variant	Exon 8 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1411C>G	p.Arg471Gly	missense_variant	Exon 8 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1411C>G	p.Arg471Gly	missense_variant	Exon 8 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 18, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_supporting -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 471 of the LMNA protein (p.Arg471Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant lipodystrophy (PMID: 18041775). ClinVar contains an entry for this variant (Variation ID: 66824). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 34862408). This variant disrupts the p.Arg471 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18646565, 23582089, 27532257, 29943882). 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. -

Familial partial lipodystrophy, Dunnigan type Pathogenic:1

Oct 18, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM5_STR,PS4_MOD,PM2_SUP,PP3 -

Cardiovascular phenotype Pathogenic:1

Oct 31, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R471G variant (also known as c.1411C>G), located in coding exon 8 of the LMNA gene, results from a C to G substitution at nucleotide position 1411. The arginine at codon 471 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in an individual with dilated cardiomyopathy (DCM) and cardiac conduction disease, as well as in two siblings with familial partial lipodystrophy (Muschke P et al. Am. J. Med. Genet. A, 2007 Dec;143A:2810-4; Ambry internal data). Another alteration at the same codon, p.R471H (c.1412G>A), has been reported in association with laminopathy and DCM (Astejada MN et al. Acta Myol. 2007; 26(3):159-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;D;.;.;.;.;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;D;.;.
Vest4		0.95
MutPred		0.95		Loss of methylation at K470 (P = 0.0624);Loss of methylation at K470 (P = 0.0624);Loss of methylation at K470 (P = 0.0624);Loss of methylation at K470 (P = 0.0624);.;.;.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99
gMVP		0.96

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: rs28928902; hg19: chr1-156106742;