1-156130756-C-T

Variant names:

• chr1-156130756-C-T
• rs370200334
• NM_170707.4:c.496C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_170707.4(LMNA):​c.496C>T​(p.Arg166Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000942 in 1,591,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 3.06
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_170707.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156130757-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

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.496C>T	p.Arg166Trp	missense	Exon 2 of 12	NP_733821.1	P02545-1
	LMNA	NM_005572.4	MANE Plus Clinical	c.496C>T	p.Arg166Trp	missense	Exon 2 of 10	NP_005563.1	P02545-2
	LMNA	NM_001406985.1		c.496C>T	p.Arg166Trp	missense	Exon 2 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.496C>T	p.Arg166Trp	missense	Exon 2 of 12	ENSP00000357283.4	P02545-1
	LMNA	ENST00000677389.1	MANE Plus Clinical	c.496C>T	p.Arg166Trp	missense	Exon 2 of 10	ENSP00000503633.1	P02545-2
	LMNA	ENST00000368299.7	TSL:1	c.496C>T	p.Arg166Trp	missense	Exon 2 of 12	ENSP00000357282.3	P02545-6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD2 exomes AF: 0.0000236 AC: 5 AN: 212162 AF XY: 0.00000871

Gnomad AFR exome AF: 0.0000752

Gnomad AMR exome AF: 0.0000334

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000218

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.00000973 AC: 14 AN: 1439580 Hom.: 0 Cov.: 32 AF XY: 0.00000840 AC XY: 6 AN XY: 714468

African (AFR) AF: 0.00 AC: 0 AN: 32894

American (AMR) AF: 0.0000243 AC: 1 AN: 41122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38602

South Asian (SAS) AF: 0.00 AC: 0 AN: 83858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4460

European-Non Finnish (NFE) AF: 0.00000908 AC: 10 AN: 1101234

Other (OTH) AF: 0.0000336 AC: 2 AN: 59442

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
1	-	-	Charcot-Marie-Tooth disease type 2 (1)
-	1	-	Hutchinson-Gilford 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;C5676942:Restrictive dermopathy 2;C5979868:Dilated cardiomyopathy 1A (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
CardioboostCm	Uncertain	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.87
MPC		2.1
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.58
gMVP		0.93
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370200334; hg19: chr1-156100547;