1-156114921-G-T

Position:

• chr1-156114921-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001406986.1(LMNA):​c.-421G>T variant causes a 5 prime UTR premature start codon gain change. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_001406986.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 1-156114921-G-T is Pathogenic according to our data. Variant chr1-156114921-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156114921-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.3G>T	p.Met1?	start_lost	1/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.3G>T	p.Met1?	start_lost	1/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.3G>T	p.Met1?	start_lost	1/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.3G>T	p.Met1?	start_lost	1/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2017	p.Met1Ile (M1I) ATG>ATT: c.3 G>T in exon 1 of the LMNA gene (NM_170707.2). The c.3 G>T mutation in the LMNA gene has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. This mutation 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. Two mutations which affect the Met1 residue have been reported in association with laminopathies (Walter M et al., 2005; van Tintelen et al., 2007). Walter et al. identified a 15bp deletion starting at c.-3 that includes the Met1 codon in a family with symptoms of Emery-Driefuss muscular dystrophy, limb girdle muscular dystrophy with atrioventricular disturbance and dilated cardiomyopathy with conduction defects. van Tintelen et al. identified a deletion of the 5' end of the LMNA gene, including exon 1 and the Met1 codon in a family presenting with severe, early onset myocardial fibrosis. Also, c.3 G>T in the LMNA gene has been observed in other unrelated individual tested for DCM at GeneDx. Therefore, the presence of this mutation indicates an increased risk to develop DCM. However, other genetic and environmental factors influence disease expression and severity, and some mutation carriers may never become symptomatic. The variant is found in DCM panel(s)." -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2016	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 15, 2022

For these reasons, this variant has been classified as Pathogenic. 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, 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. ClinVar contains an entry for this variant (Variation ID: 200949). 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 individual(s) with autosomal dominant LMNA-related conditions (PMID: 29211919). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;.;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.084	D
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Pathogenic	0.72
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		0.96
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;