1-156137642-T-G

Variant names:

• chr1-156137642-T-G
• rs267607582
• NM_170707.4:c.1609-12T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_170707.4(LMNA):​c.1609-12T>G variant causes a 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.82

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 Likely_pathogenic. Variant got 8 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 1-156137642-T-G is Pathogenic according to our data. Variant chr1-156137642-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66855.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156137642-T-G is described in Lovd as [Likely_pathogenic]. Variant chr1-156137642-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1609-12T>G		intron_variant	Intron 9 of 11	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1609-12T>G		intron_variant	Intron 9 of 9	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1609-12T>G		intron_variant	Intron 9 of 11	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1609-12T>G		intron_variant	Intron 9 of 9		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

May 02, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in LMNA is an intronic variant located in intron 9. This variant is absent from the population database gnomAD v4.0. The variant has been reported to segregate with a phenotype consistent with LMNA-related cardiac disease in multiple individuals in one family (PMID: 18611980). At least one patient with this variant displayed a large proportion of abnormal nuclei in fibroblasts, which is highly specific for a laminopathy (PMID: 30420677). The results from an in silico splicing predictor (SpliceAI) indicate that this variant may impact splicing by disrupting the acceptor splice site of intron 9 of LMNA. This prediction is confirmed by non-quantiative RNA and protein expression assays demonstrating that the variant impacts splicing by creating a de novo acceptor site leading to 11 bp retention of intron 9 (PMID: 18611980). The aberrant transcript is expected to produce a premature stop codon in biologically relevant exon 10/12 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PP1_Moderate, PP4_Moderate, PM2_Supporting. -

Heart-hand syndrome, Slovenian type Pathogenic:1

Oct 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		0.89		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607582; hg19: chr1-156107433;