rs794728598

chr1-156114921-G-Achr1-156114921-G-Cchr1-156114921-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):c.3G>A(p.Met1?) variant causes a start lost change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.89

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_170707.4 (LMNA) was described as [Likely_pathogenic] in ClinVar as 200949
• PP5: Variant 1-156114921-G-A is Pathogenic according to our data. Variant chr1-156114921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 488705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156114921-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.3G>A	p.Met1?	start_lost	1/12	ENST00000368300.9
LMNA	NM_005572.4	c.3G>A	p.Met1?	start_lost	1/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.3G>A	p.Met1?	start_lost	1/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.3G>A	p.Met1?	start_lost	1/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398804 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689832

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

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

Invitae

Oct 13, 2023

This sequence change affects the initiator methionine of the LMNA mRNA. The next in-frame methionine is located at codon 187. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with LMNA-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 488705). This variant disrupts a region of the LMNA protein in which other variant(s) (p.Lys32del, p.Asn39Ser. p.Glu82Lys) have been determined to be pathogenic (PMID: 17377071, 18551513, 20160190, 20980393, 21632249). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Nov 30, 2020

We observed the genetic variant c.3G>A (p.M1I) in a 43-y.o. male proband, diagnosed with left ventricular non-compaction and dilatation of all cardiac chambers. The c.3G>A genetic variant leads to mutation in the initiation codon (PVS1 criteria). Neither population data (PM2 criteria) nor functional studies are available for this variant. Online in silico tools predict the p.M1I to have the deleterious effect (PP3 criteria). Additionally, this variant was previously reported as pathogenic (PP5). Two more nucleotide changes were reported in this codon, all of them leading to methionine-isoleucine amino acid substitution. We classify the c.3G>A genetic variant as pathogenic due to the combination of PVS1, PM2, PP3, and PP5 criteria. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2021

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Alters the initiator methionine codon, and the resultant protein would be described as "p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 488705; ClinVar) -

Dilated cardiomyopathy 1A Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

KTest Genetics, KTest

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.084	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D
Polyphen		0.84	P;.;P;P;.
Vest4		0.59
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);Gain of catalytic residue at M1 (P = 0.0507);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.87
gMVP		0.94

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: rs794728598; hg19: chr1-156084712;