1-156136985-G-A

Variant names:

• chr1-156136985-G-A
• rs11575937
• NM_170707.4:c.1445G>A
• LMNA p.Arg482Gln

GermlineCancer (beta)

Variant summary

Our verdict is

Pathogenic

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 14 classification points (ACMG Germline Pathogenicity v2019): 14P and 0B. PS3PM1PM2_SupportingPM5PP2PP5_Strong

The NM_170707.4(LMNA):c.1445G>A (p.Arg482Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000248 (AC=4) in the gnomAD database across 1,614,080 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000241. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV002070468: Transgenic mice expressing the p.Arg482Gln variant showed increase blood insulin levels, reduced insulin sensitivity, and impaired adipocyte differentiation, consistent with the clinical phenotypes observed in patients (PMID:19201734)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R482P: Likely_pathogenic (ClinVar VariationId 3359050, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R482L: Uncertain_significance (ClinVar VariationId 14490, 1 star); p.R482= (synonymous): Likely_benign (ClinVar VariationId 3387012, 1 star); p.R482= (synonymous): Likely_benign (ClinVar VariationId 4690634, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20 U:2 O:2
• Conservation: PhyloP100: 4.19
• Publications: 151 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 1A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, ClinGen
• Emery-Dreifuss muscular dystrophy 2, autosomal dominant

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial partial lipodystrophy, Dunnigan type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• restrictive dermopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
• Hutchinson-Gilford progeria syndrome

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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 2B1

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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 14 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV002070468: Transgenic mice expressing the p.Arg482Gln variant showed increase blood insulin levels, reduced insulin sensitivity, and impaired adipocyte differentiation, consistent with the clinical phenotypes observed in patients (PMID: 19201734).; SCV000065011: Transgenic mice with the p.Arg482Gln variant of LMNA have a phenotype consistent FPLD (Wojtanik 2009).; SCV000885655: Transgenic mice expressing the human variant protein shows increase blood insulin levels, reduced insulin sensitivity, and impaired adipocyte differentiation, consistent with the clinical phenotypes in patients (Wojtanik 2009).; SCV002513142: Transgenic mice harboring this variant develop a syndrome that resembles many of the features of human familial partial lipodystrophy (Wojtanik et al., 2009);; SCV000548869: Experimental studies have shown that this missense change affects LMNA function (PMID: 19201734, 20130076).; SCV000882464: Indeed, functional studies of the Arg482Gln mutant protein, as well as the Arg482Trp protein, demonstrated a failure of adipocyte cell differentiation (16415042). A transgenic mouse harboring the Arg482Gln mutation recapitulates the FPLD2 phenotype and studies confirmed a lack of adipocyte renewal (19201734).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).
• PM2: Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000241 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R482P: Likely_pathogenic (ClinVar VariationId 3359050, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R482L: Uncertain_significance (ClinVar VariationId 14490, 1 star); p.R482= (synonymous): Likely_benign (ClinVar VariationId 3387012, 1 star); p.R482= (synonymous): Likely_benign (ClinVar VariationId 4690634, 1 star)
• PP2: Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.100). ClinVar shows strong pathogenic missense enrichment: 343 P/LP and 16 B/LB missense entries (ratio 21.4×).
• PP5: ClinVar 0-star pathogenic — supporting (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s). ClinVar submissions strongly and reliably favor pathogenicity (15/17 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMNA	NM_170707.4	MANE Select	c.1445G>A	p.Arg482Gln	missense	Exon 8 of 12	NP_733821.1	P02545-1
	LMNA	NM_005572.4	MANE Plus Clinical	c.1445G>A	p.Arg482Gln	missense	Exon 8 of 10	NP_005563.1	P02545-2
	LMNA	NM_001406985.1		c.1445G>A	p.Arg482Gln	missense	Exon 8 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.1445G>A	p.Arg482Gln	missense	Exon 8 of 12	ENSP00000357283.4	P02545-1
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.1445G>A	p.Arg482Gln	missense	Exon 8 of 10	ENSP00000503633.1	P02545-2
	LMNA	ENST00000368299.7	TSL:1	c.1445G>A	p.Arg482Gln	missense	Exon 8 of 12	ENSP00000357282.3	P02545-6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000224 Hom.: 0

Bravo AF: 0.0000302

Local populations

WBBC (Westlake BioBank for Chinese) pilot AF: 0.000112 AC: 1 AN: 8960 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (7)
5	-	-	Familial partial lipodystrophy, Dunnigan type (5)
-	1	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
1	-	-	Dilated cardiomyopathy 1A (1)
1	-	-	Emery-Dreifuss muscular dystrophy 3, autosomal recessive (1)
1	-	-	Hutchinson-Gilford syndrome;C0406585:Lethal tight skin contracture syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5979868:Dilated cardiomyopathy 1A (1)
1	-	-	Laminopathy (1)
1	-	-	Lipodystrophy - childhood onset (1)
1	-	-	LMNA-related disorder (1)
1	-	-	Monogenic diabetes (1)
-	1	-	Primary dilated cardiomyopathy (1)
-	-	-	Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5979868:Dilated cardiomyopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
CardioboostCm	Benign	0.0086
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.060
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.56
Sift	Benign	0.037	D
Sift4G	Uncertain	0.035	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.77
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11575937;

hg19: chr1-156106776;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar