rs41313880

chr1-156130617-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_170707.4(LMNA):c.357C>T(p.Arg119=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,613,826 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: LMNA NM_170707.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.01863
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:33 O:1
• Conservation: PhyloP100: 0.736

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-156130617-C-T is Benign according to our data. Variant chr1-156130617-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48062.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=1, Benign=18, Uncertain_significance=1}. Variant chr1-156130617-C-T is described in Lovd as [Benign]. Variant chr1-156130617-C-T is described in Lovd as [Likely_benign]. Variant chr1-156130617-C-T is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=0.736 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00311 (4549/1461474) while in subpopulation NFE AF= 0.00326 (3623/1111842). AF 95% confidence interval is 0.00317. There are 12 homozygotes in gnomad4_exome. There are 2170 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.357C>T	p.Arg119=	splice_region_variant, synonymous_variant	2/12	ENST00000368300.9
LMNA	NM_005572.4	c.357C>T	p.Arg119=	splice_region_variant, synonymous_variant	2/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.357C>T	p.Arg119=	splice_region_variant, synonymous_variant	2/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.357C>T	p.Arg119=	splice_region_variant, synonymous_variant	2/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152234 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00312 AC: 784 AN: 251304 Hom.: 2 AF XY: 0.00297 AC XY: 403 AN XY: 135898

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00311 AC: 4549 AN: 1461474 Hom.: 12 Cov.: 31 AF XY: 0.00298 AC XY: 2170 AN XY: 727050

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152352 Hom.: 2 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74496

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.00353

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00279 Hom.: 0

Bravo AF: 0.00227

EpiCase AF: 0.00267

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:33 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2012	Arg119Arg in exon 2 of LMNA: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and has been identified in 0.3% (24/7020) of European American chromosomes from a broad population by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs413 13880). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2018	Variant summary: LMNA c.357C>T (p.Arg119Arg) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0033 in 277140 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 13-fold of the estimated maximal expected allele frequency for a pathogenic variant in LMNA causing Cardiomyopathy phenotype (0.00025), strongly suggesting that the variant is benign. The variant, c.357C>T, has been reported in the literature and classified as likely benign by the authors (Dorschner_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x likely benign/benign, 1x VUS). Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not provided Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28798025, 20848652, 25637381, 24055113) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LMNA: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -

Emery-Dreifuss muscular dystrophy Benign:2

Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Primary dilated cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 27, 2022	- -

Dilated cardiomyopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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Charcot-Marie-Tooth disease type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LMNA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital muscular dystrophy due to LMNA mutation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hutchinson-Gilford syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mandibuloacral dysplasia with type A lipodystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Lethal tight skin contracture syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Familial partial lipodystrophy, Dunnigan type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	17
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.019
dbscSNV1_RF	Benign	0.69
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: rs41313880; hg19: chr1-156100408;