rs397517905

Positions:

• chr1-156134808-C-G
• chr1-156134808-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_170707.4(LMNA):​c.643C>G​(p.Leu215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L215P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.594

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 6 ACMG points.

• PM1: In a hotspot region, there are 4 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 chr1-156134809-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65764.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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39857548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.643C>G	p.Leu215Val	missense_variant	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.643C>G	p.Leu215Val	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.643C>G	p.Leu215Val	missense_variant	4/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.643C>G	p.Leu215Val	missense_variant	4/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 29, 2014

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostCm	Benign	0.074
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Benign	0.36
DEOGEN2	Uncertain	0.57	.;.;.;D;.;.;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.080	N;.;N;N;N;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.56	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;D;T
Polyphen		0.057	B;.;B;B;.;.;P;.;.
Vest4		0.66
MutPred		0.58		Loss of catalytic residue at L215 (P = 0.0866);Loss of catalytic residue at L215 (P = 0.0866);Loss of catalytic residue at L215 (P = 0.0866);Loss of catalytic residue at L215 (P = 0.0866);Loss of catalytic residue at L215 (P = 0.0866);.;.;.;.;
MVP		0.99
MPC		1.0
ClinPred		0.068	T
GERP RS		2.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		4.0
Varity_R		0.071
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: rs397517905; hg19: chr1-156104599;