rs57520892

Variant names:

• chr1-156137204-G-A
• rs57520892
• NM_170707.4:c.1580G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-156137204-G-A
• chr1-156137204-G-C
• chr1-156137204-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_170707.4(LMNA):​c.1580G>A​(p.Arg527His) variant causes a missense change. The variant allele was found at a frequency of 0.0000257 in 1,598,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R527C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:4 O:1
• Conservation: PhyloP100: 5.39

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 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr1-156137204-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP5: Variant 1-156137204-G-A is Pathogenic according to our data. Variant chr1-156137204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14499.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=9, not_provided=1}. Variant chr1-156137204-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1580G>A	p.Arg527His	missense_variant	Exon 9 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1580G>A	p.Arg527His	missense_variant	Exon 9 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1580G>A	p.Arg527His	missense_variant	Exon 9 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1580G>A	p.Arg527His	missense_variant	Exon 9 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000410 AC: 9 AN: 219426 Hom.: 0 AF XY: 0.0000168 AC XY: 2 AN XY: 119110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000616

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000204

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000242 AC: 35 AN: 1446066 Hom.: 0 Cov.: 32 AF XY: 0.0000251 AC XY: 18 AN XY: 718406

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000214

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000474 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000413 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Other:1

Jun 19, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 16, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: failure to restore p16ink4A/pRB pathway signaling, increased sensitivity to ionizing radiation, and destabilization of heterochromatin-associated proteins (Filesi et al., 2005; Nitta et al., 2006; di Masi et al., 2008); 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: 23891399, 24375749, 25637381, 18604166, 12075506, 14627682, 12788894, 16046620, 19764019, 28663758, 25823658, 19084400, 17848409, 31589614, 32041611, 32376792, 34135346, 33422685, 10939567, 33038109, 15473259, 29854317, 25324471, 16809772, 10080180, 31383942) -

Mandibuloacral dysplasia with type A lipodystrophy Pathogenic:3

Jan 09, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Missense variants have been reported to result in gain of function and dominant negative effects, and are associated with childhood-onset disease or skeletal muscle involvement while protein truncating variants have been reported to result in loss of function and haploinsufficiency, and are associated with the 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, mainly associated with Emery-Dreifuss muscular dystrophy and LMNA-related dilated cardiomyopathy (PMID: 20301609). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated lamin tail domain (NCBI conserved domain]. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent pathogenic variant associated with mandibuloacral dysplasia (MIM#248370) (MAD) and has been reported in at least ten homozygous or compound heterozygous in individuals with MAD (ClinVar; PMIDs: 14627682, 17848409, 28663758, 29557732). The association of this variant with cardiomyopathy is currently unclear (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mandibuloacral dysplasia Pathogenic:1 Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Feb 08, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg527His variant in LMNA has been reported in the homozygous or compound heterozygous state in 10 individuals with mandiculoacral dysplasia (MAD) and segregated with disease in 5 affected individuals from 4 families (Novelli 2002, Shen 2003, Simha 2003, Garavelli 2009). It has also been identified in 6/31826 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 14499). In vitro functional studies support an impact on protein function (Novelli 2002, Amati 2004, Filesi 2005, Nitta 2006, Lombardi 2007, Meaburn 2007, di Masi 2008, Evangelisti 2015). Three additional variants involving this codon (p.Arg527) have been identified in individuals with MAD (Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MAD. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PM5_Strong, PP1_Strong, PS3_Moderate, BP4. -

Charcot-Marie-Tooth disease Pathogenic:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mandibuloacral dysplasia with type A lipodystrophy, atypical Pathogenic:1

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 527 of the LMNA protein (p.Arg527His). This variant is present in population databases (rs57520892, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive mandibuloacral dysplasia (PMID: 12075506, 14627682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14499). 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%. Experimental studies have shown that this missense change affects LMNA function (PMID: 12075506, 18604166, 25324471, 25823658). For these reasons, this variant has been classified as Pathogenic. -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Pathogenic:1

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

May 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 527 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499). -

Primary dilated cardiomyopathy Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 527 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499). -

Cardiovascular phenotype Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R527H variant (also known as c.1580G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1580. The arginine at codon 527 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in several homozygous or compound heterozygous individuals with autosomal recessive mandibuloacral dysplasia (MAD), and individuals with MAD plus overlapping laminopathy features and atypical myopathies (Shen JJ et al. J. Med. Genet., 2003 Nov;40:854-7; Lombardi F et al. J. Clin. Endocrinol. Metab., 2007 Nov;92:4467-71; Garavelli L et al. Am. J. Med. Genet. A, 2009 Oct;149A:2258-64; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138; J&eacute;ru I et al. Genes (Basel), 2021 Sep;12; Turkyilmaz A et al. Clin Dysmorphol. 2021 Jan;30(1):10-16). Heterozygous carrier family members and healthy population cohort participants have been reported to be unaffected with MAD or other laminopathy-related phenotypes (Dron JS et al. BMC Med Genomics, 2020 02;13:23; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138). In assays testing LMNA function, this variant showed a functionally abnormal result (Novelli G et al. Am. J. Hum. Genet., 2002 Aug;71:426-31; Evangelisti C et al. Oncotarget, 2015 Apr;6:7424-37; di Masi A et al. Cell Cycle, 2008 Jul;7:2030-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of mandibuloacral dysplasia (MAD) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathy-related phenotypes is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
CardioboostCm	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D;.;.;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.1	L;.;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.033	D;.;D;D;D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T
Polyphen		0.066	B;.;B;B;.;.;B;.;.
Vest4		0.79
MVP		0.99
MPC		0.44
ClinPred		0.14	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.64

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: rs57520892; hg19: chr1-156106995;