rs57983345

Variant names:

• chr1-156115034-A-G
• rs57983345
• NM_170707.4:c.116A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-156115034-A-G
• chr1-156115034-A-T

Variant summary

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

The NM_170707.4(LMNA):​c.116A>G​(p.Asn39Ser) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N39K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.33

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 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr1-156115033-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2202857.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.994
• PP5: Variant 1-156115034-A-G is Pathogenic according to our data. Variant chr1-156115034-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 66791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156115034-A-G is described in Lovd as [Pathogenic]. Variant chr1-156115034-A-G is described in Lovd as [Pathogenic]. Variant chr1-156115034-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-156115034-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.116A>G	p.Asn39Ser	missense_variant	Exon 1 of 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: 1447038 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718414

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: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Apr 07, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N39S pathogenic variant in the LMNA gene was first initially reported in an individual with EDMD (Benedetti et al., 2007), and subsequently reported as an apparently de novo variant in additional individuals with LMNA-related disorders (Quijano-Roy et al., 2008; Pasqualin et al., 2014). The N39S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and different missense variants at the same position (N39Y/K) have been previously reported in association with muscular dystrophy (Prigogine et al., 2010; Tan et al., 2015). Additionally, missense variants in nearby residues (L35V/P; R41C/S; A43T) have been reported in the Human Gene Mutation Database in association with LMNA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LMNA c.116A>G (p.Asn39Ser) missense variant results in the substitution of asparagine at amino acid position 39 with serine. Across a selection of the available literature, the c.116A>G variant has been identified in at least ten individuals with muscular disorders, and in five of these it was found to be de novo (PMID: 18551513; PMID: 24508248; PMID: 26098624; PMID: 33250842; PMID: 32571898; PMID: 32528171; PMID: 34240052). Functional studies demonstrated that this variant causes the variant LMNA protein to aggregate (PMID: 34862408). Other pathogenic missense changes at the same codon, including p.Asn39Lys and p.Asn39Tyr, have been reported in multiple individuals with muscular disorders. This variant is located within the N-terminal Coil 1A coiled-coil domain which is a part of the larger central rod region and is thought to be involved in head to tail interactions of nuclear lamins and in facilitating the unwinding of molecules into separate strands (PMID: 30083363; PMID: 15476822). Multiple lines of in silico predictions suggest that this variant may have a deleterious effect on the gene or gene product. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.116A>G (p.Asn39Ser) variant is classified as pathogenic for LMNA-related muscular disorders. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 39 of the LMNA protein (p.Asn39Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy (PMID: 17377071, 18551513, 21520333, 24508248). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 66791). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

LMNA-related disorder Pathogenic:1

Mar 02, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2, PM5 moderated, PM6 strong, PP3 supporting -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Pathogenic:1

Sep 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest a damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000066791 /PMID: 18551513). The variant has been previously reported as de novo in a similarly affected individual (PMID: 18551513). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 18551513, 24508248). Different missense changes at the same codon (p.Asn39Asp, p.Asn39His, p.Asn39Ile, p.Asn39Lys, p.Asn39Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000649203, VCV000935833, VCV002098082, VCV002202857 /PMID: 20837309, 21632249, 26098624, 30083363, 34240052 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;.;H;H;H
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		1.0
MutPred		0.96		Gain of phosphorylation at N39 (P = 0.0422);Gain of phosphorylation at N39 (P = 0.0422);Gain of phosphorylation at N39 (P = 0.0422);Gain of phosphorylation at N39 (P = 0.0422);Gain of phosphorylation at N39 (P = 0.0422);
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.99

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: rs57983345; hg19: chr1-156084825;