rs57207746

Positions:

• chr1-156134860-G-A

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.695G>A​(p.Gly232Glu) variant causes a missense 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. 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. G232R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.92

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, 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 chr1-156134859-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 285122.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, 0.906
• PP5: Variant 1-156134860-G-A is Pathogenic according to our data. Variant chr1-156134860-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134860-G-A is described in Lovd as [Pathogenic]. Variant chr1-156134860-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.695G>A	p.Gly232Glu	missense_variant	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.695G>A	p.Gly232Glu	missense_variant	4/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.695G>A	p.Gly232Glu	missense_variant	4/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.695G>A	p.Gly232Glu	missense_variant	4/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

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

Dec 25, 2019

This sequence change replaces glycine with glutamic acid at codon 232 of the LMNA protein (p.Gly232Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly232 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 18564364, 24349489), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect LMNA protein function (PMID: 25982065, 23077635, 16772334, 29676528, 29753763). This variant has been observed in individual(s) with childhood-onset muscular dystrophy (PMID: 29893365, 10939567). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66925). This variant is not present in population databases (ExAC no frequency). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2015

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Benign	0.098
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;.;.;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.17	T;D;T;D;T;T;D;D;T
Polyphen		0.32	B;.;D;B;.;.;D;.;.
Vest4		0.84
MutPred		0.74		Loss of MoRF binding (P = 0.0605);Loss of MoRF binding (P = 0.0605);Loss of MoRF binding (P = 0.0605);Loss of MoRF binding (P = 0.0605);Loss of MoRF binding (P = 0.0605);.;.;.;.;
MVP		0.90
MPC		2.3
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.5
Varity_R		0.70
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs57207746; hg19: chr1-156104651;