rs138251566

Positions:

chr10-86706685-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_007078.3(LDB3):c.1051A>G(p.Thr351Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,612,664 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 2 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: -1.38

Variant links:

Genes affected

LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

LDB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01079753).

BP6

Variant 10-86706685-A-G is Benign according to our data. Variant chr10-86706685-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36942.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=2}. Variant chr10-86706685-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.1051A>G	p.Thr351Ala	missense_variant	8/14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.1051A>G	p.Thr351Ala	missense_variant	8/14	1	NM_007078.3	ENSP00000355296	P4	O75112-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000544

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000453

AC:

112

AN:

247106

Hom.:

AF XY:

0.000484

AC XY:

AN XY:

134344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000929

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000614

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000501

AC:

732

AN:

1460460

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

726558

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000806

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000568

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000289

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000530

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000501

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000772

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: LDB3 c.1051A>G (p.Thr351Ala) results in a non-conservative amino acid change in 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 0.00045 in 247106 control chromosomes. The observed variant frequency is approximately 14.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Dilated Cardiomyopathy With Left Ventricular Noncompaction phenotype (3.1e-05), strongly suggesting that the variant is benign. c.1051A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy and ARVC, without strong evidence for causality (Kadiyska_2007, Lopez-Ayala_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: three submitters classified as VUS while five classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 05, 2013	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. LDB3 p.Thr351Ala Arbustini et al (2007) submitted a brief report to Human Genetics on this variant as a novel variant seen in a 62-year-old male with “noncompaction dilated cardiomyopathy.” I also found a conference abstract in Italian that appears to report the variant in a patient with LVNC (Tripodi et al 2010 71st Congresso Nazionale della Societa Italiana di Cardiologia). A translation via Google translate indicates the authors report the p.Thr351Ala variant in a 41-year old male with LVNC. No segregation or function data was provided in either report. Vatta et al (2003) reported a variant (p.Ile352Met) at the neighboring codon that was present in all five family members with DCM and absent in 200 controls. They predicted that this variant would “abolish an alpha-helix a short beta-sheet.” Another nearby variant (p.Thr350Ile) has been reported in a case of a child with Barth Syndrome (Marziliano et al 2007). That patient also had a nonsense variant in TAZ. Interestingly, the patient’s brother and father both carried the p.Thr350Ile LDB3 variant and had non-compaction on echo, though not severe enough to make diagnostic criteria for LVNC. Arbustini et al (2007) also reported that another patient with “noncompaction dilated cardiomyopathy” had a variant in another nearby codon (p.Thr358Ala). The p.Thr351Ala variant in LDB3 is a non conservative amino acid change with a polar, neutral Threonine replaced with a non polar neutral Alanine. In silico analysis (PolyPhen and SIFT) predicts the variant to be benign and tolerated respectively. While the cases reviewed above do not include HCM, variants in LDB3 have been implicated in HCM. Tripodi et al (2010) did not observe the variant in either 150 or 300 control individuals (difficult to tell in the translated text). No other control data is available, however the variant is not reported in dbSNP (checked March 2nd, 2011) Based on these data, this variant may cause cardiomyopathy, though there is insufficient data available to support predictive genetic testing in at-risk family members. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 28, 2017	p.Thr351Ala in exon 10 of LDB3: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including multiple mamm als. In addition, this variant has been identified in 0.08% (27/34356) of Latino and 0.06% (78/124442) of European chromosomes Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org/; dbSNP rs138251566), and in individuals wi th different, non-overlapping cardiomyopathies, including two individuals with a disease-causing variant sufficient to cause their disease (LMM data). -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	Reported in association with non-compaction dilated cardiomyopathy (Arbustini et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 36942; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31078652, 17438604, 33633783, 23299917, 27896284, 20474083, 25616123, 25041374, 29517769) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LDB3: BP4 -

Dilated cardiomyopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Feb 26, 2020

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 11, 2021

- -

Myofibrillar myopathy 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

LDB3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

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

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 16, 2017

The LDB3 Thr351Ala has been reported before in an an ARVD/C proband, and was found to cosegregate to two siblings diagnosed with ARVD/C (Lopez JM, et al., 2014). This variant has also been found in a 62yo male patient with severe dilated cardiomyopathy with non-compaction (Arbustini E, et al., 2007) and a HCM patient with another likely causal variant (LMM ClinVar; SCV000062395.4). It is present in the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency >0.0004, which is higher then expected for an inherited heart disease. We identified this variant in a HCM proband with no family history of HCM or SCD. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be non-deleterious. In summary, based on a high allele frequency in the general population and in silico tools predicting no functional affect on the protein, we classify LDB3 Thr351Ala as "likely benign". -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.18

CADD

Benign

0.029

DANN

Benign

0.34

DEOGEN2

Benign

0.17

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0071

LIST_S2

Benign

0.26

M_CAP

Benign

0.012

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.055

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.040

REVEL

Uncertain

0.46

Sift

Benign

0.45

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.059

MVP

0.53

ClinPred

0.013

GERP RS

-9.3

Varity_R

0.023

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.

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