rs267607581

Positions:

• chr1-156137651-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_170707.4(LMNA):​c.1609-3C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-156137651-C-G is Pathogenic according to our data. Variant chr1-156137651-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156137651-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_005572.4	c.1609-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000677389.1	NP_005563.1
LMNA	NM_170707.4	c.1609-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000368300.9	NP_733821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1609-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.1609-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2022	Identified in a family with LGMD in several symptomatic individuals but also in several asymptomatic adults (Chrestian et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, and published RNA studies and mini-gene assay support a significant splicing defect (Chrestian et al., 2008; Ito et al., 2017); This variant is associated with the following publications: (PMID: 25525159, 24503780, 18714801, 24846508, 32376792, 24459210, 10939567, 36138163, 28679633) -

Charcot-Marie-Tooth disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2023

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 18714801). ClinVar contains an entry for this variant (Variation ID: 66856). This variant is also known as IVS9-3C>G. This variant has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 18714801, 24503780). 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 falls in intron 9 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

LMNA-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The LMNA c.1609-3C>G variant is predicted to interfere with splicing. This variant has been reported in a large French Canadian family in which some individuals had a limb girdle type muscle weakness as well as cardiac conduction phenotype (Chrestian. et al. 2008. PubMed ID: 18714801). However, this variant was also found in at least 3 individuals in this family with a clinical evaluation of no muscle weakness or cardiac symptoms (age of clinical workup was 30-40). RNA studies did indicate that this variant resulted in exon skipping of exon 10 and an in-frame deletion of 30 amino acids and a mini-gene assay also indicates this variant results in aberrant splicing (Ito et al. 2017. PubMed ID: 28679633). This variant was also reported in a single patient with a clinical diagnosis and family history of dilated cardiomyopathy (Pugh et al. 2014. PubMed ID: 24503780). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Dilated cardiomyopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 23, 2020

The c.1609-3C>G variant in LMNA has been identified in one individual with limb girdle muscular dystrophy and was found to segregate with disease in at least 3 affected relatives (Chrestian 2008 PMID: 18714801), all of whom had cardiac involvement. It was also identified by our laboratory in one individual with DCM (LMM data) and has reported in ClinVar by other clinical laboratories (Variation ID 66856). This variant was absent from large population studies. Two studies using patient RNA and a cell-based splicing assay have independently shown that this variant results in the skipping of exon 10, leading to an in-frame deletion of 30 amino acids (Chrestian 2008 PMID: 18714801, Ito 2017 PMID: 28679633). In summary, although additional studies are required to fully establish its clinical significance, the c.1609-3C>G variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PS4_Supporting, PP1. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jan 25, 2017

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2023

The c.1609-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 10 in the LMNA gene. This variant was detected in a proband reported to have limb girdle muscular dystrophy and cardiac conduction disease and segregated with disease in several relatives with primarily cardiac findings including cardiac conduction disease, dysrhythmia, dilated cardiomyopathy or sudden death with or without muscle weakness. RNA studies on a sample from the proband indicated abnormal splicing leading to skipping of exon 10 (Chrestian N et al. Can J Neurol Sci, 2008 Jul;35:331-4). This variant was also detected in an individual from a dilated cardiomyopathy cohort (Pugh TJ et al. Genet. Med. 2014 Aug;16(8):601-8). This alteration was also detected in a Charcot-Marie-Tooth cohort; however, clinical details were limited (Volodarsky M et al. J Med Genet, 2021 Apr;58:284-288). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607581; hg19: chr1-156107442;