1-156136033-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_170707.4(LMNA):c.1069G>T(p.Asp357Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. D357N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.06

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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr1-156136033-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1403065.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1069G>T	p.Asp357Tyr	missense_variant	6/12	ENST00000368300.9
LMNA	NM_005572.4	c.1069G>T	p.Asp357Tyr	missense_variant	6/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1069G>T	p.Asp357Tyr	missense_variant	6/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1069G>T	p.Asp357Tyr	missense_variant	6/10		NM_005572.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 476820). 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 replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 357 of the LMNA protein (p.Asp357Tyr). -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Nov 30, 2017

p.Asp357Tyr (c.1069G>T) in exon 6 of the LMNA gene (NM_170707.3; chr1-156105824-G-T) SCICD Classification: variant of uncertain significance based on lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LMNA: Pathogenic variants in LMNA cause clinically variable diseases, called the laminopathies. These include dilated cardiomyopathy (DCM), which is typically accompanied by conduction system disease and/or arrhythmias. Sudden cardiac death can occur before the onset of LV dilation, warranting early consideration of an ICD. Other laminopathies include Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome and lipodystrophies, among others. Modeling data indicates that pathogenic variants in the coil 2B domain likely disrupts this region's native significant negative electrostatic potential, destabilizing the lamin A/C protein (Gangemi, 2013). Case data (not including our patient): none ClinVar: not present Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." Conservation data: The aspartic acid at codon 357 is highly, but not completely conserved across species. Neighboring amino acids are similiarly conserved. Nearby pathogenic variants at this codon or neighboring codons: Another variant at this codon, p.Asp357His, is present in ClinVar but is not classified. The synonymous variant, p.Asp357Asp, is classified as likely benign by Invitae. Modeling data indicates that pathogenic variants in the coil 2B domain likely disrupts this region's native significant negative electrostatic potential, destabilizing the lamin A/C protein (Gangemi, 2013). Fujimori et al (2008) sequenced LMNA, TNNT2 and SERPINC1 in a Japanese patient with both antithrombin deficiency and DCM. p.Pro439Thr in SERPINC1 (for antithrombin deficiency) and p.Asp357His in LMNA were identified. This patient had sustained VT and an ICD was placed. His monozygotic twin brother had maternal cousin had a pacemaker due to complete AV-block. This variant was also present in 2 of his children with DCM. His monozygotic twin brother did not have genetic testing. The study posits that change of an acidic aspartic acide with a basic histidine would be detrimental to protein function given that codon 357 lies within a highly-conserved region of the rod domain. This domain forms a patch of pronounced negative electrostatic potential. This has not been confirmed with functional studies. Stallmeyer et al (2012) reported two members of a family with DCM and conduction system disease had a different variant at this codon, p.Asp357Ala. Alanine also has hydrophobic properties, and may impact the lamin A/C protein in the same manner proposed by Fujimori et al (2008). In our case, the exchange of a negatively-charged amino acid with a hydrophobic tyrosine does not result in a drastic change in polarity. Population data: There is no variation at codon 357 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 34.9x whereas in exomes it is 82.8x. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostCm	Uncertain	0.22
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.011	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D;D;D;D;D
Polyphen		0.93	P;.;D;D;.;.;D;.
Vest4		0.75
MutPred		0.53		Gain of phosphorylation at D357 (P = 0.0501);Gain of phosphorylation at D357 (P = 0.0501);Gain of phosphorylation at D357 (P = 0.0501);Gain of phosphorylation at D357 (P = 0.0501);Gain of phosphorylation at D357 (P = 0.0501);.;.;.;
MVP		0.93
MPC		2.3
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.66
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs267607567; hg19: chr1-156105824;