1-156115096-C-T

Position:

• chr1-156115096-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_170707.4(LMNA):​c.178C>T​(p.Arg60Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R60G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.59

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 10 ACMG points.

• PM1: In a hotspot region, there are 9 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 chr1-156115097-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2722945.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ: 2.3673 (greater than the threshold 3.09). Trascript score misZ: 3.0905 (greater than threshold 3.09). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. GenCC has associacion of the gene with familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 1-156115096-C-T is Pathogenic according to our data. Variant chr1-156115096-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179969.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.178C>T	p.Arg60Cys	missense_variant	1/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.178C>T	p.Arg60Cys	missense_variant	1/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.178C>T	p.Arg60Cys	missense_variant	1/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.178C>T	p.Arg60Cys	missense_variant	1/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446562 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718166

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg60 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10580070, 12196663, 20041886). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 179969). 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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the LMNA protein (p.Arg60Cys). -

Dilated cardiomyopathy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Several pathogenic variants have been reported with reduced penetrance in families with autosomal dominant Emery-Dreifuss muscular dystrophy or other LMNA-related disorders (PMID: 20301609). Age-related penetrance has been reported for LMNA-related dilated cardiomyopathy (PMID: 20301717). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated filament domain (NCBI). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg60Gly) and p.(Arg60Pro) have been reported in at least six unrelated families with dilated cardiomyopathy (DCM) and/or cardiac conduction defects, with or without lipodystrophy, diabetes or axonal peripheral neuropathy (PMIDs: 10580070, 19768759, 12196663, 20041886, 28199729, 28408391, 32245113, 32740430, 33029862). The p.(Arg60Pro) variant has also been reported as likely pathogenic by a clinical testing laboratory (ClinVar). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as VUS by clinical testing laboratories (ClinVar), however two of the individuals have DCM and one individual has an unspecified type of cardiomyopathy and arrhythmia (personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 25, 2014

The Arg60Cys variant in LMNA has not been previously reported in individuals wit h cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that the Arg60Cys variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. Additionally, another variant has been reported at this position (Arg60Gly) and is classified as likely pathogenic for DCM with or without conduction disease a nd lipodystrophy (Fatkin 1999, van der Kooi 2002, Subramanyam 2009, Carboni 2010 , Zwerger 2013), raising the possibility that a change at this position may not be tolerated. In summary, the clinical significance of the Arg60Cys variant is u ncertain. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
CardioboostCm	Uncertain	0.15
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.7	M;.;M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.040	D;D;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D;D
Polyphen		0.96	D;.;D;D;.
Vest4		0.72
MutPred		0.69		Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);Loss of disorder (P = 0.0153);
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.98

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: rs28928900; hg19: chr1-156084887;