chr1-156137233-G-A

Position:

• chr1-156137233-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000368300.9(LMNA):​c.1608+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA ENST00000368300.9 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05964912 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156137233-G-A is Pathogenic according to our data. Variant chr1-156137233-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1608+1G>A		splice_donor_variant, intron_variant		ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1608+1G>A		splice_donor_variant, intron_variant		ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1608+1G>A		splice_donor_variant, intron_variant		1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1608+1G>A		splice_donor_variant, intron_variant			NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 01, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 effect 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 cardiac and myopathy disorders (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease. There are multiple phenotypes associated with this gene, however dilated cardiomyopathy type 1A (CMD1A) (MIM#115200) and Emery-Dreifuss muscular dystrophy 2 (MIM#181350; formerly limb-girdle muscular dystrophy type 1B (LGMD1B)) are inherited in a dominant manner (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The majority of individuals published with this variant were diagnosed with LGMD1B, however a small number of cases were not reported with skeletal muscle involvement and considered to have CMD1A only. It has been suggested that individuals initially referred for DCM also be assessed for a history of mild muscle weakness (PMID: 19446900). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least four alternative variants, at the same nucleotide and in the surrounding splice region, have previously been reported in more than ten unrelated individuals with either LGMD1B or CMD1A (ClinVar, PMIDs: 24459210, 24915601, 29693488, 31744510, 33304817). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in at least eight probands, predominantly in association LGMD1B, however it has also been reported for CMD1A only (ClinVar, VCGS, PMIDs: 13129702, 15678000, 19446900, 31931689). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregation with disease in two LGMD1B families and one CMD1A family, in a total of seven affected genotyped individuals and two obligate carriers (VCGS, PMIDs: 15678000, 19446900, 31931689). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Experiments using transplanted heart tissue from an LGMD1B individual showed increased levels of phosphorylated ERK1/2 compared to controls, similar to the increased activity observed in in vitro and in vivo models of other pathogenic LMNA variants (PMID: 22068161). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Neuromuscular disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 10, 2014

The 1608+1G>A variant in LMNA gene was absent from large population studies but has been reported in one individual with limb-girdle muscular dystrophy type 1B (LGMD1B) with DCM and segregated with disease in 4 affected family members inclu ding 2 obligate carriers (Ambrosi 2009). It was also detected in 2 additional in dividuals with LGMD1B and conduction system disease as well as one affected fami ly member (Ben Yaou 2005). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. In summary, this variant meets our criter ia to be classified as pathogenic for LGMD1B in an autosomal dominant manner (ht tp://www.partners.org/personalizedmedicine/LMM) based upon segregation studies, absence from controls, predicted impact to the protein. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

ClinVar contains an entry for this variant (Variation ID: 66853). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as IVS9+1G>A. Disruption of this splice site has been observed in individual(s) with autosomal dominant limb-girdle muscular dystrophy (PMID: 15678000, 19446900). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.1608+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the LMNA gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). This variant (also referred to as IVS9+1G>A) has been detected in individuals with features consistent with laminopathies, including dilated cardiomyopathy, cardiac conduction disease, and limb-girdle muscular dystrophy, and has shown segregation with disease features in families (Ambrosi P et al. Int J Cardiol, 2009 Nov;137:e75-6; Ben Yaou R et al. Rev Neurol (Paris), 2005 Jan;161:42-54; Ramchand J et al. J Am Heart Assoc, 2020 Jan;9:e013346). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: -30
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607592; hg19: chr1-156107024;