rs397517888

chr1-156136074-C-CATGG

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.1112_1115dup(p.Glu372AspfsTer55) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32

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 1-156136074-C-CATGG is Pathogenic according to our data. Variant chr1-156136074-C-CATGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48030.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.1112_1115dup	p.Glu372AspfsTer55	frameshift_variant	6/10	ENST00000677389.1
LMNA	NM_170707.4	c.1112_1115dup	p.Glu372AspfsTer55	frameshift_variant	6/12	ENST00000368300.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1112_1115dup	p.Glu372AspfsTer55	frameshift_variant	6/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1112_1115dup	p.Glu372AspfsTer55	frameshift_variant	6/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	Although the c.1112_1115dupTGGA pathogenic variant in the LMNA gene has not been reported toour knowledge, this variant causes a shift in reading frame starting at codon Glutamic acid 372,changing it to an Aspartic acid, and creating a premature stop codon at position 55 of the new readingframe, denoted: p.Glu372AspfsX55. This pathogenic variant is expected to result in either anabnormal, truncated protein product or loss of protein from this allele through nonsense-mediatedmRNA decay. Other frameshift variants in the LMNA gene have been reported in HGMD inassociation with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.1112_1115dupTGGAvariant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. In summary, c.1112_1115dupTGGA in the LMNA gene is interpreted as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 26, 2019	- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 48030). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu372Aspfs*55) 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, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 11, 2014

The Glu372fs variant in LMNA has been identified by our laboratory in one Caucas ian adult with DCM and ventricular tachycardia as well in his relative with AFib and AV block. Data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the pro tein?s amino acid sequence beginning at position 372 and lead to a premature ter mination codon 55 amino acids downstream. This alteration is then predicted to l ead to a truncated or absent protein. Heterozygous loss of function of the LMNA gene is an established disease mechanism in individuals with DCM. In addition, a nother frameshift variant starting at the same codon, but leading to a premature stop codon 108 amino acids downstream, has been reported in one individual with DCM and was absent in 300 control chromosomes (Parks 2008). In summary, this va riant is likely to be pathogenic, though additional studies are required to full y establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517888; hg19: chr1-156105865;