1-156134964-T-C

Position:

• chr1-156134964-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000368300.9(LMNA):​c.799T>C​(p.Tyr267His) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y267C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.06

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 Pathogenic. Variant got 19 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, 14 uncertain in ENST00000368300.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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). GenCC has associacion of 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, 0.992
• PP5: Variant 1-156134964-T-C is Pathogenic according to our data. Variant chr1-156134964-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156134964-T-C is described in Lovd as [Pathogenic]. Variant chr1-156134964-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.799T>C	p.Tyr267His	missense_variant	4/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.799T>C	p.Tyr267His	missense_variant	4/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.799T>C	p.Tyr267His	missense_variant	4/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.799T>C	p.Tyr267His	missense_variant	4/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2015	p.Tyr267His (Y267H) TAT>CAT: c.799 T>C in exon 4 of the LMNA gene (NM_170707.2). The Y267H mutation in the LMNA gene has been reported in association with cardiac conduction disease and DCM (Carboni N et al., 2008; Lakdawala N et al., 2012). Carboni et al. identified Y267H in a woman with atrio-ventricular block and high serum creatine kinase levels, and it was subsequently identified in 5 other relatives with cardiac defects. Y267H 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. Mutations in this residue (Y267C) and in nearby residues (L263P, S268P) have been reported in association with laminopathy, further supporting the functional importance of this position and this region of the protein. The variant is found in DCM panel(s). -
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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 22, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr267 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 14684700, 18926329), which suggests that this may be a clinically significant amino acid residue. 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: 48084). This missense change has been observed in individual(s) with autosomal dominant Emery-Dreifuss muscular dystrophy, cardiac conduction disease and/or dilated cardiomyopathy (PMID: 18337098, 22464770, 22806367, 27532257, 29693488). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 267 of the LMNA protein (p.Tyr267His). -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 15, 2010

The Tyr267His variant has been previously reported in one individual with atrio- ventricular block as well as 5 family members with DCM +/- conduction system def ects (Carboni 2008). The variant was absent from 200 control chromosomes, sugges ting that the variant is disease causing. In addition, tyrosine (Tyr) at positi on 267 is conserved across evolutionary distant species, further supporting a pa thogenic role. In summary, this variant meets our criteria for pathogenicity (ht tp://pcpgm.partners.org/LMM) based upon segregation studies, absence from contro ls and evolutionary conservation of the affected amino acid. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2017

The p.Y267H variant (also known as c.799T>C), located in coding exon 4 of the LMNA gene, results from a T to C substitution at nucleotide position 799. The tyrosine at codon 267 is replaced by histidine, an amino acid with some similar properties. This alteration was shown to segregate with disease in a family with rhythm abnormalities and muscle involvement (Carboni N et al. Neuromuscul. Disord., 2008 Apr;18:291-8). This alteration has also been identified in dilated cardiomyopathy (DCM) cohorts (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Uncertain	0.71
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.
Vest4		0.96
MutPred		0.93		Loss of phosphorylation at Y267 (P = 0.0523);Loss of phosphorylation at Y267 (P = 0.0523);Loss of phosphorylation at Y267 (P = 0.0523);Loss of phosphorylation at Y267 (P = 0.0523);Loss of phosphorylation at Y267 (P = 0.0523);.;.;.;
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.89
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: rs267607593; hg19: chr1-156104755;