rs80338938

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The ENST00000368300.9(LMNA):c.1698+13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,547,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

LMNA
ENST00000368300.9 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4O:2

Conservation

PhyloP100: 3.30

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-156137756-C-A is Pathogenic according to our data. Variant chr1-156137756-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14485.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=4, not_provided=2}. Variant chr1-156137756-C-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.25167367). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_005572.4 linkuse as main transcript	c.1711C>A	p.Arg571Ser	missense_variant	10/10	ENST00000677389.1	NP_005563.1
LMNA	NM_170707.4 linkuse as main transcript	c.1698+13C>A		intron_variant		ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000677389.1 linkuse as main transcript	c.1711C>A	p.Arg571Ser	missense_variant	10/10		NM_005572.4	ENSP00000503633		P02545-2
LMNA	ENST00000368300.9 linkuse as main transcript	c.1698+13C>A		intron_variant		1	NM_170707.4	ENSP00000357283	P1	P02545-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000333

AC:

AN:

150320

Hom.:

AF XY:

0.0000125

AC XY:

AN XY:

80064

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000901

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000696

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1395630

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

688440

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000352

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000161

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2024	Segregates with cardiac disease in a single family with a variable presentation of atrioventricular block, atrial fibrillation, and dilated cardiomyopathy, and three individuals also had mildly elevated CK levels without overt skeletal muscle disease; however, only the LMNA gene was sequenced and in vitro functional studies were not included (PMID: 10580070); Reported in an individual with early onset atrial fibrillation and a family history of DCM; segregation testing was not performed (PMID: 23483212); Identified in an individual with EDMD, although cDNA nomenclature was not provided to confirm the variant is the same (PMID: 36282542); Reported as p.(R571S) using an alternate transcript of the gene, referred to as the lamin C isoform (PMID: 8344919); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20301717, 24846508, 11102973, 8344919, 32685188, 30199159, 36282542, 28686329, 23483212, 10580070) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Dilated cardiomyopathy 1A

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 02, 1999	- -

Laminopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301609). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to serine. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is present in isoform C, but absent in isoform A (NM_170707.4). Both isoforms are expressed in almost all cells and tissues, however the high degree of tissue-specificity and the resulting different phenotypes observed in laminopathies are not completely elucidated (PMID: 27529282). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 7 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: p.(Arg571His) with 39 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. For instance, p.(Arg571Cys) has been reported as a VUS by multiple clinical testing laboratories (ClinVar). It has also been reported in an individual with neuropathy and myopathy, and his unaffected mother (PMID: 15965218). In addition, it has been reported in at least two individuals with DCM or conduction defect, and 3 others without specific clinical information (PMIDs: 31521807, 31383942). p.(Arg571Pro) has been reported in one individual with conduction defect, and another without specific clinical information (PMID: 31383942). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant and c.1711_1712delinsTC, both predicted to result in the same amino acid change, have been reported as pathogenic by a clinical testing laboratory and a VUS by five other clinical testing laboratories (ClinVar). They included seven individuals without diagnosis of cardiovascular disease, an individual with muscle weakness and ptosis, an individual with a clinical diagnosis of LGMD, and multiple individuals on testing for an indication of cardiomyopathy and arrhythmia (ClinVar, personal communication). The missense variant has also been reported in at least three unrelated individuals with lipodystrophy, DCM associated with conduction-system disease or myopathy (PMIDs: 28686329, 10580070, 36282542). (I) 0901 - This variant has strong evidence for segregation with disease. It has been reported as heterozygous in the proband and seven affected members of a family with DCM associated with conduction-system disease (PMID: 10580070). (SP) 1010 - Functional evidence for this variant is inconclusive. Functional studies using lymphoblasts from a proband showed normal expression pattern of lamin A and C transcripts and protein (PMID: 28686329). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change falls in intron 10 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs80338938, gnomAD 0.01%). This variant has been observed in individual(s) with dilated cardiomyopathy and conduction defects and/or lipodystrophy (PMID: 10580070, 28686329). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1711C>A (p.Arg571Ser). ClinVar contains an entry for this variant (Variation ID: 14485). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Nov 05, 2023

This sequence change in LMNA is predicted to replace arginine with serine at codon 571 in a lamin C-specific residue, p.(Arg571Ser). The variant is non-coding in the lamin A transcript (NM_170707.4:c.1698+13C>A). The arginine residue is located in the lamin C tail domain (PMID: 8344919). There is a large physicochemical difference between arginine and serine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.007% (4/57,466 alleles) in the European (non-Finnish) population. This variant has been reported in at least one proband with atrial fibrillation (PMID: 23483212). The missense variant (without the underlying nucleotide description) has been reported in an individual with a phenotype consistent with Emery-Dreifuss Muscular Dystrophy (PMID: 23483212). The variant has been reported to segregate with atrial fibrillation and/or dilated cardiomyopathy in a large multigenerational family (PMID:10580070). The variant hindered myogenic differentiation (cell fusion and myotube formation) in in vitro assays in mouse cells indicating that this variant impacts protein function (PMID: 30199159). Computational evidence is uninformative for the missense substitution (REVEL = 0.485) and no impact on splicing is predicted for the variant (SpliceAI). The same amino acid change (p.Arg571Ser), resulting from a different nucleotide change c.1711_1712delinsTC, has been reported in siblings with generalised lipodystrophy (PMID: 28686329). The variant has been reported as likely pathogenic/pathogenic previously (ClinVar, Shariant). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PM2_Supporting, PS3_Supporting. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 16, 2023

This missense variant (p.Arg571Ser; c.1711C>A) occurs at the C-terminal end of the lamin C protein (NM_005572.3) encoded by the LMNA gene and corresponds to intronic position c.1698+13C>A in lamin A transcript (NM_170707.3). Computational prediction tools indicate that this missense variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy and conduction system disease in one large multigenerational family (PMID: 10580070). Five carriers were affected with rhythm disturbance and three carriers were affected with both rhythm disturbance and dilated cardiomyopathy. Three unaffected carriers were under age 30. Affected individuals in this family showed mild cardiac phenotype and lacked skeletal-muscle symptoms. A different variant causing the same protein effect (c.1711_1712delinsTC; p.Arg571Ser) has been reported in two individuals affected with juvenile-onset generalized lipodystrophy in one family (PMID: 28686329). This variant has been identified in 5/150320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.1698+13C>A intronic variant results from a C to A substitution 13 nucleotides after coding exon 10 in the LMNA gene. In an alternate isoform, this variant results in a missense change (NM_005572:c.1711C>A, p.R571S) which has been detected in affected individuals from a family with dilated cardiomyopathy and cardiac arrhythmia, and in additional individuals with skeletal myopathy and cardiac arrhythmia (Fatkin D et al. N Engl J Med, 1999 Dec;341:1715-24; Ng KK et al. Australas Med J, 2013 Feb;6:75-8de Las Heras JI et al. Hum Mol Genet, 2023 Mar;32:1010-1031). This variant is not considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

0.073

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.56

T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.51

MutationTaster

Benign

1.0

D;D;D;D;D;N;N;N;N

PROVEAN

Benign

0.30

N;.;N

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;.;D

Sift4G

Benign

0.27

T;D;T

Polyphen

0.36

B;.;P

Vest4

0.49

MutPred

0.54

.;.;Gain of phosphorylation at R490 (P = 0.0073);

MVP

0.90

ClinPred

0.26

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over