Variant 1-156130658-G-A details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr1-156130657-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2733992.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.812

PP5

Variant 1-156130658-G-A is Pathogenic according to our data. Variant chr1-156130658-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200934.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=13}. Variant chr1-156130658-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.398G>A	p.Arg133Gln	missense_variant	2/12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 linkuse as main transcript	c.398G>A	p.Arg133Gln	missense_variant	2/10	ENST00000677389.1	NP_005563.1	P02545-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9 linkuse as main transcript	c.398G>A	p.Arg133Gln	missense_variant	2/12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.398G>A	p.Arg133Gln	missense_variant	2/10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152170

Hom.:

0

Cov.:

32

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251388

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

9

AN:

1461746

Hom.:

0

Cov.:

32

AF XY:

0.00000825

AC XY:

6

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152170

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

0

Bravo

AF:

0.00000378

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2022	Reported in association with cardiomyopathy and/or arrhythmia (Kumar et al., 2016a; Kumar et al., 2016b; Hou et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In vitro functional studies demonstrate endothelial cell dysfunction (Sayed et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10939567, 32727917, 34999423, 27884249, 27506821, 31980526) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 19, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg133Gln When we initially reviewed the variant in 2011 it was discussed at a the Stanford Center for Inherited Cardiovascular Disease team meeting and we felt that the absence in controls, supporting segregation data, and other variants at the same codon were all sufficient to consider it likely pathogenic, though we would have preferred even more data supporting pathogenicity. Other variants in this gene have been associated with familial dilated cardiomyopathy, often with a higher incidence of conduction system disease, atrial arrhythmias, ventricular ectopy, and sudden death, all of which may occur prior to apparent LV dilatation or dysfunction. Variants in LMNA have also been associated with a wide range of other conditions, including Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy, both of which often have cardiac involvement. Other conditions associated with this gene include Charcot-Marie-Tooth disease, Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome. These don't classically have cardiac involvement, but in some cases they do. Segregation data from our center includes a family in which the variant segregates with disease in three affected siblings (though two of the three siblings are identical twins) and the affected child of one of those siblings. Other variants at this same codon and the neighboring codon have been reported in association with disease. Brown et al (2001) reported p.Arg133Pro in an individual with limb-girdle muscular dystrophy who was diagnosed at 7 years of age. Her cardiac phenotype was noted to include atrial fibrillation and a pacemaker at 32 years of age. A different variant at this codon, p.Arg133Leu, has been reported in three unrelated cases with a progeroid phenotype (Chen et al 2003, Caux et al 2003). In one of those cases the variant was de novo. One of these individuals had hypertrophic cardiomyopathy and skeletal muscle hypertrophy. Lupsa et al 2010 reported a 9yo boy with lipodystrophy and p.Arg133Leu with dilated cardiomyopathy. Another variant at a neighboring codon (p.Ala132Pro) has been reported in association with dilated cardiomyopathy (Karkkainen et al 2006). p.Arg133Gln is a semi conservative amino acid change with a polar, positive Arginine replaced with a polar, neutral Glutamine. In silico analysis with PolyPhen2 predicts the variant to be possibly damaging. Many other variants in the same domain have been reported in association with dilated cardiomyopathy (Pasotti et al 2008). There is no variation at codon 133 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 16th, 2015). Mean coverage is >50. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	LMNA: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

LMNA-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2024

The LMNA c.398G>A variant is predicted to result in the amino acid substitution p.Arg133Gln. This variant has been reported in families with cardiomyopathy (Kumar et al. 2016. PubMed ID: 27884249; Hou et al. 2020. PubMed ID: 31980526). Functional studies in induced pluripotent stem cells-derived endothelial cells from a patient with the p.Arg133Gln variant exhibit endothelial dysfunction (Sayed et al. 2020. PubMed ID: 32727917). Two different substitutions of the same amino acid (p.Arg133Leu and p.Arg133Pro) have been reported to be causative for lipodystrophy, Werner syndrome, and Emery-Driefuss muscular dystrophy (Jacob et al. 2005. PubMed ID: 16174718; Caux et al. 2003. PubMed ID: 12629077; Brown et al. 2001. PubMed ID: 11503164). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 133 of the LMNA protein (p.Arg133Gln). This variant is present in population databases (rs60864230, gnomAD 0.002%). This missense change has been observed in individual(s) with myopathic gait, elevated CK, and muscle weakness and dilated cardiomyopathy (PMID: 27506821; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200934). 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%. This variant disrupts the p.Arg133 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11503164, 12629077, 12927431, 14615128, 16174718). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Emery-Dreifuss muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 03, 2023

This missense variant replaces arginine with glutamine at codon 133 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Induced pluripotent stem cells derived from a carrier individual exhibited endothelial cell dysfunction, as seen by impaired angiogenesis and nitric oxide production, suggesting that this variant may affect downstream signaling pathways in endothelial cells (PMID: 32727917). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 32727917, 34999423; communication with an external laboratory, ClinVar SCV000262236.7). This variant has also been reported in an individual affected with cardiomyopathy (PMID: 31980526), in an individual affected with ventricular tachycardia and death (PMID: 27506821), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (communication with an external laboratory, ClinVar SCV000262236.7), and in an individual affected with arrhythmogenic right ventricular dysplasia (Elshafie, 2023). This variant has been identified in 3/282776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg133Leu and p.Arg133Pro, are associated with autosomal recessive laminopathy phenotypes (Clinvar variation ID: 14488 and 14508), indicating that arginine at this position is important for LMNA protein function. The available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2B1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Congenital muscular dystrophy due to LMNA mutation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Dilated cardiomyopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Hutchinson-Gilford syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Mandibuloacral dysplasia with type A lipodystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Lethal tight skin contracture syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Familial partial lipodystrophy, Dunnigan type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 2023

This missense variant replaces arginine with glutamine at codon 133 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Induced pluripotent stem cells derived from a carrier individual exhibited endothelial cell dysfunction, as seen by impaired angiogenesis and nitric oxide production, suggesting that this variant may affect downstream signaling pathways in endothelial cells (PMID: 32727917). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 32727917, 34999423; communication with an external laboratory, ClinVar SCV000262236.7). This variant has also been reported in an individual affected with cardiomyopathy (PMID: 31980526), in an individual affected with ventricular tachycardia and death (PMID: 27506821), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (communication with an external laboratory, ClinVar SCV000262236.7), and in an individual affected with arrhythmogenic right ventricular dysplasia (Elshafie, 2023). This variant has been identified in 3/282776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg133Leu and p.Arg133Pro, are associated with autosomal recessive laminopathy phenotypes (Clinvar variation ID: 14488 and 14508), indicating that arginine at this position is important for LMNA protein function. The available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2023

The p.R133Q variant (also known as c.398G>A), located in coding exon 2 of the LMNA gene, results from a G to A substitution at nucleotide position 398. The arginine at codon 133 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual from a cardiovascular disease cohort (presumably with cardiomyopathy) who was treated for ventricular tachycardia and heart failure (Kumar S et al. J. Am. Coll. Cardiol., 2016 11;68:2299-2307; Kumar S et al. Circ Arrhythm Electrophysiol, 2016 08;9). This variant has also been detected in individuals reported to have dilated cardiomyopathy; however, details were limited and some reports may overlap (Cho S et al. Stem Cell Res. 2022 Jan;59:102657; Sayed N et al. Sci Transl Med. 2020 07;12(554)). This amino acid position is highly 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. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

CardioboostCm

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.19

D

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

31

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

.;.;.;D;.;.;.;T;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.78

D

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.19

D

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.26

D

MutationAssessor

Uncertain

2.8

M;.;M;M;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.65

T

PROVEAN

Uncertain

-2.5

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.14

T;T;T;T;T;T;T;T;T

Sift4G

Uncertain

0.054

T;T;D;D;T;T;T;T;T

Polyphen

0.43

B;.;P;P;.;.;P;.;.

Vest4

0.86

MVP

0.85

MPC

1.8

ClinPred

0.99

D

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.70

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

1-156130658-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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