rs876657649

Positions:

• chr1-156136074-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000368300.9(LMNA):​c.1110C>G​(p.Asp370Glu) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D370G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.45

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 15 ACMG points.

• PS1: Transcript ENST00000368300.9 (LMNA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000368300.9
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.974
• PP5: Variant 1-156136074-C-G is Pathogenic according to our data. Variant chr1-156136074-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228270.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1110C>G	p.Asp370Glu	missense_variant	6/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1110C>G	p.Asp370Glu	missense_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.1110C>G	p.Asp370Glu	missense_variant	6/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.1110C>G	p.Asp370Glu	missense_variant	6/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Laminopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 11, 2015

The p.Asp370Glu variant in LMNA has been identified by our laboratory in 1 indiv idual with muscle weakness and progressive contractures, and occurred de novo. T his variant was absent from large population studies. Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinic al significance, the p.Asp370Glu variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;D;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.9	M;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;T;D;T;T;T
Polyphen		1.0	D;.;D;D;.;.;D;.
Vest4		0.92
MutPred		0.84		Loss of ubiquitination at K366 (P = 0.1576);Loss of ubiquitination at K366 (P = 0.1576);Loss of ubiquitination at K366 (P = 0.1576);Loss of ubiquitination at K366 (P = 0.1576);Loss of ubiquitination at K366 (P = 0.1576);.;.;.;
MVP		0.95
MPC		2.1
ClinPred		0.99	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.87
gMVP		0.98

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: rs876657649; hg19: chr1-156105865;