rs1553265433

Positions:

• chr1-156135208-G-A
• chr1-156135208-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.832G>A​(p.Ala278Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,270 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A278P) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.04

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr1-156135208-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 435769.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). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. GenCC has associacion of the 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, 0.877
• PP5: Variant 1-156135208-G-A is Pathogenic according to our data. Variant chr1-156135208-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 995175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135208-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.832G>A	p.Ala278Thr	missense_variant	5/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.832G>A	p.Ala278Thr	missense_variant	5/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.832G>A	p.Ala278Thr	missense_variant	5/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.832G>A	p.Ala278Thr	missense_variant	5/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152270 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.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74396

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala278 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26098624, 27708273; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 995175). This variant has been observed in individual(s) with autosomal dominant LMNA-related conditions (PMID: 20472316). 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 alanine with threonine at codon 278 of the LMNA protein (p.Ala278Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -

LMNA-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2023

The LMNA c.832G>A variant is predicted to result in the amino acid substitution p.Ala278Thr. This variant was reported in a family of individuals with atrial fibrillation phenotypes and was reported to segregate with disease (Beckmann et al. 2010. PubMed ID: 20472316). A similar amino acid substitution (p.Ala278Pro) has also been reported in individuals with an Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy phenotypes (Table 2, Tan et al. 2015. PubMed ID: 26098624; Reddy et al. 2016. PubMed ID: 27708273). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 05, 2019

Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Segregation with disease in affected individuals from a single family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
CardioboostCm	Uncertain	0.78
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M;.;M;M;M;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D;T;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.
Vest4		0.85
MutPred		0.61		Gain of phosphorylation at A278 (P = 0.0177);Gain of phosphorylation at A278 (P = 0.0177);Gain of phosphorylation at A278 (P = 0.0177);Gain of phosphorylation at A278 (P = 0.0177);Gain of phosphorylation at A278 (P = 0.0177);.;.;.;
MVP		0.97
MPC		1.8
ClinPred		0.92	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.55
gMVP		0.93

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: rs1553265433; hg19: chr1-156104999;