chr1-156135968-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_170707.4(LMNA):c.1004G>T(p.Arg335Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335P) 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.18

Publications

0 publications found

Variant links:

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

LMNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 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 chr1-156135968-GG-CC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 451712.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4 link	c.1004G>T	p.Arg335Leu	missense_variant	Exon 6 of 12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 link	c.1004G>T	p.Arg335Leu	missense_variant	Exon 6 of 10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 link	c.1004G>T	p.Arg335Leu	missense_variant	Exon 6 of 12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 link	c.1004G>T	p.Arg335Leu	missense_variant	Exon 6 of 10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

CardioboostCm

Uncertain

0.63

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;.;.;D;.;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.7

M;.;M;M;M;.;.;.

PhyloP100

8.2

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.0

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;D;D;D;D;D;T;D

Sift4G

Benign

0.091

T;D;T;D;T;D;D;D

Polyphen

0.036

B;.;P;P;.;.;P;.

Vest4

0.92

MutPred

0.64

Loss of MoRF binding (P = 0.0287);Loss of MoRF binding (P = 0.0287);Loss of MoRF binding (P = 0.0287);Loss of MoRF binding (P = 0.0287);Loss of MoRF binding (P = 0.0287);.;.;.;

MVP

0.90

MPC

2.3

ClinPred

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.79

gMVP

0.97

Mutation Taster

=4/96

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over