1-156137144-GC-GCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_170707.4(LMNA):c.1526dup(p.Thr510TyrfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S507S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LMNA NM_170707.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 1.79

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156137144-G-GC is Pathogenic according to our data. Variant chr1-156137144-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 48041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_005572.4	c.1526dup	p.Thr510TyrfsTer42	frameshift_variant	9/10	ENST00000677389.1
LMNA	NM_170707.4	c.1526dup	p.Thr510TyrfsTer42	frameshift_variant	9/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1526dup	p.Thr510TyrfsTer42	frameshift_variant	9/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1526dup	p.Thr510TyrfsTer42	frameshift_variant	9/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461102 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2016	c.1526dupC: p.Thr510TyrfsX42 in exon 9 of the LMNA gene (NM_170707.2). The c.1526dupC pathogenic variant in the LMNA gene has been reported in one individual with DCM, reported as c.1526dupC or p.Thr510TyrfsX41 using alternate nomenclature (van Rijsingen IAW et al., 2013). The c.1526insC pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant causes a shift in reading frame starting at codon Threonine 510, changing it to a Tyrosine, and creating a premature stop codon at position 42 of the new reading frame, denoted p.Thr510TyrfsX42. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift pathogenic variants in the LMNA gene have been reported in association with cardiomyopathy. Therefore, the presence of this pathogenic variant indicates an increased risk to develop a familial form of cardiomyopathy/laminopathy. However, other genetic and environmental factors influence disease expression and severity, and some pathogenic variant carriers may never become symptomatic. The variant is found in CARDIOMYOPATHY panel(s). -
not provided, flagged submission	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 08, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 48041). This premature translational stop signal has been observed in individual(s) with LMNA-related diseases (PMID: 20848652, 23183350, 23702046, 24503780, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr510Tyrfs*42) in the LMNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 22, 2009

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.1526dupC pathogenic mutation, located in coding exon 9 of the LMNA gene, results from a duplication of C at nucleotide position 1526, causing a translational frameshift with a predicted alternate stop codon (p.T510Yfs*42). This alteration has been reported in several dilated cardiomyopathy (DCM) cohorts and a muscular dystrophy cohort, and it has been shown to segregate with DCM and conduction disease in one family (Scharner J et al. Hum. Mutat. 2011;32:152-67; Saj M et al. BMC Med. Genet. 2013;14:55; Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med. 2017;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs58013325; hg19: chr1-156106935;