rs863225270

chr1-156114998-C-Gchr1-156114998-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_170707.4(LMNA):c.80C>G(p.Thr27Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,447,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T27I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.93

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 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156114998-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 804298.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, LMNA
• BP4: Computational evidence support a benign effect (MetaRNN=0.42354885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.80C>G	p.Thr27Ser	missense_variant	1/12	ENST00000368300.9
LMNA	NM_005572.4	c.80C>G	p.Thr27Ser	missense_variant	1/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.80C>G	p.Thr27Ser	missense_variant	1/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.80C>G	p.Thr27Ser	missense_variant	1/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447890 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 718966

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal familial ventricular fibrillation Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Aug 12, 2015

The LMNA Thr27Ser is a novel variant. It is absent from both the 1000 genomes project (http://www.1000genomes.org/) and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified LMNA Thr27Ser in a clinically unaffected female, whose brother has idiopathic VF. Both patients also have an additional variant (DSP Tyr2396Asn) which is classified as a variant of "uncertain significance". Interestingly, a different rare variant at the same position (Thr27Ile) has been reported in a a family with autosomal limb-girdle muscular dystrophy (Nzwalo H, et al., 2013). Predictions from in silico tools are contradictory. SIFT and MutationTaster predict the amino acid substitution to be "deleterious" and "disease-causing", respectively. PolyPhen2 predicts this variant to be "benign". Based on its absence in the general population and our limited familial data, we classify LMNA Thr27Ser as a variant of "uncertain significance". -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 05, 2022

This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 25481314; Invitae). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 27 of the LMNA protein (p.Thr27Ser). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 217834). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). This variant disrupts the p.Thr27 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 23703017, 25256213), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
CardioboostCm	Benign	0.011
BayesDel_addAF	Benign	0.0045	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
Dann	Benign	0.94
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.73	N;.;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.47	N;N;N;N;N
REVEL	Pathogenic	0.76
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0020	B;.;B;B;.
Vest4		0.53
MutPred		0.21		Gain of phosphorylation at T27 (P = 0.0822);Gain of phosphorylation at T27 (P = 0.0822);Gain of phosphorylation at T27 (P = 0.0822);Gain of phosphorylation at T27 (P = 0.0822);Gain of phosphorylation at T27 (P = 0.0822);
MVP		0.68
MPC		0.86
ClinPred		0.64	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.32
gMVP		0.91

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: rs863225270; hg19: chr1-156084789;