rs267607545

Positions:

• chr1-156136121-G-A
• chr1-156136121-G-C
• chr1-156136121-G-T

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.1157G>A​(p.Arg386Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.96

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 Pathogenic. Variant got 17 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, 11 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 chr1-156136120-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 647241.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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 1-156136121-G-A is Pathogenic according to our data. Variant chr1-156136121-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156136121-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.1157G>A	p.Arg386Lys	missense_variant, splice_region_variant	6/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1157G>A	p.Arg386Lys	missense_variant, splice_region_variant	6/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1157G>A	p.Arg386Lys	missense_variant, splice_region_variant	6/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1157G>A	p.Arg386Lys	missense_variant, splice_region_variant	6/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	Observed in one family with Emery-Dreifuss muscular dystrophy (Bonne et al., 2000); Published functional studies demonstrate a damaging effect as RT-PCR analysis shows the variant results in two transcripts, one of normal size coding for the R386K missense variant and a larger mRNA coding for a truncated protein as a result of abnormal splicing (Bonne et al., 2000); Published functional studies demonstrate increased fractions of soluble mutant lamin A protein associated with nuclear deformation compared to wild-type and immunofluorescence showed significant aberrant localization of mutant LMNA in transfected cells (Zwerger et al., 2013; Ostlund et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12783988, 12649505, 27884249, 23029315, 11792809, 23427149, 20848652, 10939567) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2023

This variant disrupts the p.Arg386 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23427149; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 66782). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 386 of the LMNA protein (p.Arg386Lys). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant muscular dystrophy (PMID: 10939567, 27884249, 31069529). It has also been observed to segregate with disease in related individuals. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 10939567). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

-

This variant is not observed in gnomAD population database. Different amino acid change (Arg386Gly) as a known pathogenic variant at the same position has been reported. This variant affects the last nucleotide of exon 6 and a study by Bonne et al. showed that this variant causes aberrant splicing, which leads to formation of an aberrant transcript with retention of intron 6 further leading to the formation of a truncated protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;D;.;.;.;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;H;H;H;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;N
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;T;D;D;T
Polyphen		1.0	D;.;D;D;.;.;D;.;.
Vest4		0.87
MutPred		0.77		Gain of ubiquitination at R386 (P = 4e-04);Gain of ubiquitination at R386 (P = 4e-04);Gain of ubiquitination at R386 (P = 4e-04);Gain of ubiquitination at R386 (P = 4e-04);Gain of ubiquitination at R386 (P = 4e-04);.;.;.;.;
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.90
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607545; hg19: chr1-156105912;