NM_170707.4:c.1357C>T

Variant names:

• chr1-156136413-C-T
• rs58932704
• NM_170707.4:c.1357C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.1357C>T​(p.Arg453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001251976: Functional studies have shown significant effects of this variant on protein function (e.g. PMID 21173262, 14749366, 20980393, 25948554)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 2.00
• Publications: 93 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: Ambry Genetics, Orphanet, G2P
• familial partial lipodystrophy, Dunnigan type

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

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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• atrioventricular block

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Charcot-Marie-Tooth disease type 2B1

  Inheritance: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• heart-hand syndrome, Slovenian type

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Ambry Genetics, 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001251976: Functional studies have shown significant effects of this variant on protein function (e.g. PMID 21173262, 14749366, 20980393, 25948554).; SCV005904469: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 20980393)."; SCV000292719: Published functional studies demonstrate the R453W variant alters lamin A protein binding characteristics, and cells expressing the variant exhibit structural abnormalities as well as anomalous differentiation and proliferation (Depreux et al., 2015; Favreau et al., 2004; Folker et al., 2011); SCV000548859: Experimental studies have shown that this missense change affects LMNA function (PMID: 14749366, 18396274, 21173262).; SCV001251555: Functional studies in mouse myoblast C2C12 cells expressing the p.Arg453Trp variant showed poor cell differentiation, improper cell cycle exit, and excessive committment to apoptosis (Favreau et al. 2004).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 chr1-156136414-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 1-156136413-C-T is Pathogenic according to our data. Variant chr1-156136413-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170707.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	NM_170707.4	MANE Select	c.1357C>T	p.Arg453Trp	missense	Exon 7 of 12	NP_733821.1	P02545-1
	LMNA	NM_005572.4	MANE Plus Clinical	c.1357C>T	p.Arg453Trp	missense	Exon 7 of 10	NP_005563.1	P02545-2
	LMNA	NM_001406985.1		c.1357C>T	p.Arg453Trp	missense	Exon 7 of 13	NP_001393914.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	ENST00000368300.9	TSL:1 MANE Select	c.1357C>T	p.Arg453Trp	missense	Exon 7 of 12	ENSP00000357283.4	P02545-1
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.1357C>T	p.Arg453Trp	missense	Exon 7 of 10	ENSP00000503633.1	P02545-2
	LMNA	ENST00000368299.7	TSL:1	c.1357C>T	p.Arg453Trp	missense	Exon 7 of 12	ENSP00000357282.3	P02545-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 213236 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441370 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 715490

African (AFR) AF: 0.00 AC: 0 AN: 32940

American (AMR) AF: 0.00 AC: 0 AN: 41190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 38522

South Asian (SAS) AF: 0.00 AC: 0 AN: 84402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102726

Other (OTH) AF: 0.00 AC: 0 AN: 59512

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (9)
6	-	-	Emery-Dreifuss muscular dystrophy 2, autosomal dominant (6)
2	-	-	Congenital muscular dystrophy due to LMNA mutation (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
1	-	-	Dilated cardiomyopathy 1A (1)
1	-	-	Muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.62		Loss of disorder (P = 0.0026)
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.95
Mutation Taster		=0/100	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: rs58932704; hg19: chr1-156106204;