rs769210828

chr1-156135260-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_170707.4(LMNA):c.884C>T(p.Ser295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S295P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 2.72

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 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr1-156135259-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, LMNA

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.884C>T	p.Ser295Leu	missense_variant	5/12	ENST00000368300.9
LMNA	NM_005572.4	c.884C>T	p.Ser295Leu	missense_variant	5/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.884C>T	p.Ser295Leu	missense_variant	5/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.884C>T	p.Ser295Leu	missense_variant	5/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250592 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461256 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 25, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2023	Reported previously as a variant of uncertain significance in a parent whose child had a diagnosis of heterotaxy; however, no further clinical information was provided on the parent and it was unclear if the child also harbored the variant (Chetruengchai and Shotelersuk, 2022); Reported previously in an individual diagnosed with HCM; however, further clinical, family history, and segregation details were unavailable (Lopes et al., 2015); Reported previously as a variant of uncertain significance in a patient with non-ischemic cardiomyopathy and previous heart transplantation; however, further clinical and segregation information was provided (Boen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663758, 10939567, 34621001, 35581137, 25351510) -

Primary dilated cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Loeys Lab, Universiteit Antwerpen	Feb 26, 2021	This sequence change results in a missense variant in the LMNA gene (p.(Ser295Leu)) (PP2; based on GnomAd constraint matrix). The variant is described in LVOD as variant of unknown significance (LMNA_000421). This variant is present in GnomAD with a prevalence of 7/276586.This variant has been described in literature in an individual with HCM (PMID: 25351510) but was also seen in a control-population (PMID: 28663758) .The variant affects a weakly conserved nucleotide and a moderately conserved amino acid. Prediction programs classify the variant as benign (Align GVGD: C0; Polyphen-2-HumDiv: benign ; Polyphen-2-HumVar: benign; SIFT: tolerated; MutationTaster: no result) (BP4). It is located in the intermediate filament rod domain of the LMNA protein. Functional assays have not been performed for this variant. We identified this variant in a 2 unrelated patients with DCM and a third unrelated patient presenting with refractory Ventricular tachycardia in absence of structural cardiac abnormalities. No data on segregation were available. In conclusion this variant was classified as variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: BS4, PP2). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 27, 2023	This missense variant replaces serine with leucine at codon 295 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 06, 2023

This missense variant replaces serine with leucine at codon 295 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 295 of the LMNA protein (p.Ser295Leu). This variant is present in population databases (rs769210828, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20848652, 34621001; Invitae). ClinVar contains an entry for this variant (Variation ID: 518983). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The p.S295L variant (also known as c.884C>T), located in coding exon 5 of the LMNA gene, results from a C to T substitution at nucleotide position 884. The serine at codon 295 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort and dilated cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Boen HM et al. J Heart Lung Transplant, 2022 Sep;41:1218-1227). This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration has also been reported as a secondary finding in an exome cohort (Chetruengchai W et al. J Hum Genet, 2022 Mar;67:137-142). Another alteration affecting this amino acid (p.S295P, c.883T>C) has been reported in a single individual with muscular dystrophy and cardiomyopathy with conduction disease (Scharner J et al. Hum. Mutat., 2011 Feb;32:152-67). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Benign	0.034
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.071
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.41	N;.;N;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	D;D;T;T;T;T;T;T
Sift4G	Benign	0.77	T;T;T;T;T;T;T;T
Polyphen		0.014	B;.;B;B;.;.;B;.
Vest4		0.60
MutPred		0.52		Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);.;.;.;
MVP		0.96
MPC		0.88
ClinPred		0.37	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
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: rs769210828; hg19: chr1-156105051;