Variant rs56851164 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_170707.4

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4 linkuse as main transcript	c.976T>A	p.Ser326Thr	missense_variant	6/12	ENST00000368300.9	NP_733821.1	P02545-1A0A384MQX1
LMNA	NM_005572.4 linkuse as main transcript	c.976T>A	p.Ser326Thr	missense_variant	6/10	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.976T>A	p.Ser326Thr	missense_variant	6/12	1	NM_170707.4	ENSP00000357283.4		P02545-1
LMNA	ENST00000677389.1 linkuse as main transcript	c.976T>A	p.Ser326Thr	missense_variant	6/10		NM_005572.4	ENSP00000503633.1		P02545-2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

12

AN:

152092

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000560

AC:

14

AN:

249958

Hom.:

0

AF XY:

0.0000443

AC XY:

6

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.0000629

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:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461604

Hom.:

0

Cov.:

34

AF XY:

0.0000811

AC XY:

59

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.000106

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000789

AC:

12

AN:

152092

Hom.:

0

Cov.:

32

AF XY:

0.0000942

AC XY:

7

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

0

Bravo

AF:

0.0000302

ExAC

AF:

0.0000577

AC:

7

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:13Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22071332, 23142632, 16585054, 27532257, 16407522, 20627339, 28663758, 9536090, 22224630, 28518168, 31019283, 29095976, 29237690, 28679633, 24846508, 10939567, 34862408, 34240052, 36975868, 33673806, 31476771, 24503780) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 16, 2023	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2018	Variant classified as Uncertain Significance - Favor Pathogenic. The Ser326Thr v ariant in LMNA has been reported in 7 individuals with a range of cardio-muscula r manifestations, including 5 individuals with DCM and/or conduction system dise ase (CSD), 1 with late-onset scapular myopathy and CSD, and 1 with early-onset X -linked EDMD that also carried a pathogenic EMD variant (Muntoni 2006, Meune 200 6, Ito 2017, Hasselberg 2018). This variant has also been identified in 15/12614 6 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs56851164). In vitro functional studies provide some evidence that the p.Ser326Thr variant may not impact protein function (Gangemi 2013). However, these types of assays may not accurately represent biological fu nction. In addition, serine (Ser) at position 326 is not conserved in evolution with 5 species carrying a threonine (Thr), suggesting that this change may be to lerated. In summary, while there is some suspicion for a pathogenic role, the cl inical significance of the p.Ser326Thr variant is uncertain due to conflicting e vidence. ACMG/AMP Criteria applied: PM6; PS4; BP4, BS3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	Variant summary: LMNA c.976T>A (p.Ser326Thr) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249958 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (5.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.976T>A has been reported in the literature in individuals affected with Cardiomyopathy or muscle laminopathy without strong evidence of causality (e.g. Muntoni_2006, Pugh_2014, Walsh_2017, Ben Yaou_2021, Hathaway_2021, Park_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, finding no effect of the variant on laminim A aggregation (Anderson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 16585054, 23142632, 24503780, 27532257, 31019283, 34862408, 34240052, 33673806, 31383942, 25274841, 22071332). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely pathogenic (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2018	The LMNA c.976T>A; p.Ser326Thr variant (rs56851164), is reported in the literature in individuals affected with dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy (Hasselberg 2018, Muntoni 2006, Pugh 2014), and is reported in ClinVar (Variation ID: 48097). In a family with X-linked Emery-Dreifuss muscular dystrophy segregating with a STA p.Tyr105Ter variant, a presumed de novo LMNA c.976T>A; p.Ser326Thr variant was identified in one affected individual presenting with much more severe clinical symptoms than two other affected family members. This variant occurs in the functionally important coil 2B domain that mediates lamin A/C oligomerization; however, molecular dynamics modeling of the LMNA c.976T>A; p.Ser326Thr variant suggested no effect on protein dimerization, although the authors concede other mechanisms could still account for pathogenicity (Gangemi 2013). This variant is found in the non-Finnish European population with an overall allele frequency of 0.012% (15/126146 alleles) in the Genome Aggregation Database, and a recent study classified this variant as likely benign due to its population frequency above a maximum allele frequency threshold (MAF < 0.01%) expected for pathogenic variants (Walsh 2017). The serine at codon 326 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the LMNA c.976T>A; p.Ser326Thr variant is uncertain at this time. -

Dilated cardiomyopathy 1A

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene (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. LMNA-related DCM has demonstrated age-related penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (15 heterozygotes, 0 homozygotes). This variant has a European bias, with 14 of the 15 heterozygotes being observed in this population. (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated coil 2 domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. p.(Ser326Leu) has one VUS entry in ClinVar, however, serine to leucine is a major amino acid change and not comparable serine to threonine (minor change). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely pathogenic and as a VUS in patients with DCM (PMIDs: 27532257, 29095976, 30847666, 24503780). This variant has been reported as de novo in a patient with Emery-Dreifuss muscular dystrophy (EDMD) caused by a nonsense EMD gene variant. The proband had a more severe phenotype than two male relatives whom only carried the EMD gene variant (PMID: 16585054). Additionally, this variant has one likely pathogenic and nine VUS entries in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Feb 02, 2024	ACMG Criteria: PM2_P, PP5; Variant was found in heterozygous state -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Blueprint Genetics

Sep 14, 2015

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 15, 2022

This missense variant replaces serine with threonine at codon 326 of the lamin A/C proteins. 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 unspecified LMNA-associated muscular phenotype (PMID: 16407522), and in three unrelated individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 29095976). This variant has been reported as de novo in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 16585054). This and two other affected individuals from this family carried a pathogenic p.Tyr105* variant in the same gene. This variant has been reported in three additional individuals affected with Emery-Dreifuss muscular dystrophy, one individual affected with late-onset scapular myopathy and two individuals affected with dilated cardiomyopathy (PMID: 16585054). This variant has also been identified in 15/281330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. 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. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 11, 2024

This missense variant replaces serine with threonine at codon 326 of the lamin A/C proteins. 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 unspecified LMNA-associated muscular phenotype (PMID: 16407522), and in three unrelated individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 29095976). This variant has been reported as de novo in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 16585054). This and two other affected individuals from this family carried a pathogenic p.Tyr105* variant in the same gene. This variant has been reported in three additional individuals affected with Emery-Dreifuss muscular dystrophy, one individual affected with late-onset scapular myopathy and two individuals affected with dilated cardiomyopathy (PMID: 16585054). This variant has also been identified in 15/281330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The p.S326T variant (also known as c.976T>A), located in coding exon 6 of the LMNA gene, results from a T to A substitution at nucleotide position 976. The serine at codon 326 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in individuals reported to have conduction system disease and various myopathies, including dilated cardiomyopathy, late-onset scapular myopathy, and Emery-Dreifuss muscular dystrophy; however, some patients had variants in other genes and, in some cases, clinical detail and/or gene analysis were limited (Muntoni F et al. Brain. 2006;129:1260-8; Hasselberg NE et al. Eur Heart J. 2018 03;39(10):853-860Pugh TJ et al. Genet. Med. 2014;16:601-8; Peretto G et al. Ann Intern Med. 2019 10;171(7):458-463). This variant has also been detected in a hypertrophic cardiomyopathy genetic testing cohort and in cohorts not selected for the presence of LMNA-related disease, but clinical details were limited (Florwick A et al. Front Genet. 2017;8:79; Thauvin-Robinet C et al. Eur J Hum Genet. 2019 08;27(8):1197-1214; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126). 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. -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

CardioboostCm

Uncertain

0.60

BayesDel_addAF

Benign

-0.018

T

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

18

DANN

Benign

0.32

DEOGEN2

Uncertain

0.54

.;.;.;D;.;.;.;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.33

N

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.029

D

MetaRNN

Uncertain

0.55

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

MetaSVM

Benign

-0.99

T

MutationAssessor

Benign

-0.77

N;.;N;N;N;.;.;.

PrimateAI

Benign

0.46

T

PROVEAN

Benign

0.55

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

REVEL

Uncertain

0.48

Sift

Benign

1.0

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

Sift4G

Benign

0.62

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

Polyphen

0.0

B;.;B;B;.;.;B;.

Vest4

0.61

MutPred

0.76

Loss of MoRF binding (P = 0.1256);Loss of MoRF binding (P = 0.1256);Loss of MoRF binding (P = 0.1256);Loss of MoRF binding (P = 0.1256);Loss of MoRF binding (P = 0.1256);.;.;.;

MVP

0.99

MPC

0.87

ClinPred

0.020

T

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.072

gMVP

0.87

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.

rs56851164

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over