rs397517911

Positions:

• chr1-156135239-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The ENST00000368300.9(LMNA):​c.863C>G​(p.Ala288Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,448 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.05

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 Likely_pathogenic. Variant got 9 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 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, 0.903
• PP5: Variant 1-156135239-C-G is Pathogenic according to our data. Variant chr1-156135239-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48089.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156135239-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.863C>G	p.Ala288Gly	missense_variant	5/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.863C>G	p.Ala288Gly	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.863C>G	p.Ala288Gly	missense_variant	5/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.863C>G	p.Ala288Gly	missense_variant	5/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461448 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 13, 2012

The Ala288Gly variant in LMNA has not been reported in the literature nor in 2 l arge and broad populations (European and African American) screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This low frequen cy supports a pathogenic role. Our laboratory has detected this variant in one i ndividual with DCM + atrial fibrillation as well as one affected family member w ith atrial fibrillation. The constellation of features present in this family is consistent with a laminopathy. Computational analyses (biochemical amino acid p roperties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala288 Gly variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, this variant is likely to be pathog enic, though additional studies are required to establish this with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.1	M;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D
Polyphen		0.85	P;.;P;P;.;.;D;.
Vest4		0.73
MutPred		0.72		Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);Loss of stability (P = 0.0565);.;.;.;
MVP		0.87
MPC		2.0
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.53
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: rs397517911; hg19: chr1-156105030;