rs794728598

Variant names:

• chr1-156114921-G-A
• rs794728598
• NM_170707.4:c.3G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156114921-G-A
• chr1-156114921-G-C
• chr1-156114921-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_170707.4(LMNA):​c.3G>A​(p.Met1?) variant causes a start lost 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 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
• Publications: 4 publications found

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]

LMNA Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Hutchinson-Gilford progeria syndrome

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Emery-Dreifuss muscular dystrophy 3, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mandibuloacral dysplasia with type A lipodystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• atrial fibrillation

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• atypical Werner syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy due to LMNA mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal restrictive dermopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LMNA-related cardiocutaneous progeria syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Emery-Dreifuss muscular dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal semi-dominant severe lipodystrophic laminopathy

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 211 pathogenic variants. Next in-frame start position is after 187 codons. Genomic position: 156134448. Lost 0.280 part of the original CDS.
• PS1: Another start lost variant in NM_170707.4 (LMNA) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156114921-G-A is Pathogenic according to our data. Variant chr1-156114921-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 488705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.3G>A	p.Met1?	start_lost	Exon 1 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.3G>A	p.Met1?	start_lost	Exon 1 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.3G>A	p.Met1?	start_lost	Exon 1 of 10		NM_005572.4	ENSP00000503633.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31648

American (AMR) AF: 0.00 AC: 0 AN: 37188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24930

East Asian (EAS) AF: 0.00 AC: 0 AN: 36076

South Asian (SAS) AF: 0.00 AC: 0 AN: 79368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079154

Other (OTH) AF: 0.00 AC: 0 AN: 57798

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

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 28, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

KTest Genetics, KTest

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
DEOGEN2	Uncertain	0.62	.;.;.;D;.
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
PhyloP100		5.9
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
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.87
gMVP		0.94
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728598; hg19: chr1-156084712;