rs139922045

Positions:

chr10-86681778-G-A

Variant summary

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

The NM_007078.3(LDB3):c.664G>A(p.Ala222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,598,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

LDB3
NM_007078.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 2.84

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=0.05650574).

BP6

Variant 10-86681778-G-A is Benign according to our data. Variant chr10-86681778-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45551.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}. Variant chr10-86681778-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.664G>A	p.Ala222Thr	missense_variant	5/14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1 linkuse as main transcript	c.321+1621G>A		intron_variant		ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9 linkuse as main transcript	c.664G>A	p.Ala222Thr	missense_variant	5/14	1	NM_007078.3	ENSP00000355296	P4	O75112-1
LDB3	ENST00000263066.11 linkuse as main transcript	c.321+1621G>A		intron_variant		1	NM_001368067.1	ENSP00000263066		O75112-6

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000764

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000351

AC:

AN:

239460

Hom.:

AF XY:

0.000371

AC XY:

AN XY:

129462

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000359

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000713

Gnomad OTH exome

AF:

0.000348

GnomAD4 exome

AF:

0.000381

AC:

551

AN:

1446538

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

277

AN XY:

717838

show subpopulations

Gnomad4 AFR exome

AF:

0.0000608

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000764

Gnomad4 NFE exome

AF:

0.000481

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.000348

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000240

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:

0.000764

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000651

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000387

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2019	The LDB3 c.664G>A; p.Ala222Thr variant (rs139922045) is reported in the literature in individuals affected with hypertrophic cardiomyopathy, left ventricular noncompaction, myofibrillar myopathy, or inclusion body sinusitis, although it was not demonstrated to cause disease in these individuals (Lopes 2015, Miszalski-Jamka 2017, Semmler 2014, Weihl 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.07% (93/124816 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 45551). The alanine at codon 222 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the lack of clinical and functional data, the significance of the p.Ala222Thr variant is uncertain at this time. References: Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Miszalski-Jamka K et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017 Aug;10(4). Semmler AL et al. Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies. Orphanet J Rare Dis. 2014 Aug 1;9:121. Weihl CC et al. Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis. Neuromuscul Disord. 2015 Apr;25(4):289-96. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2020	Identified independently and in conjunction with additional variants in individuals with various cardiac phenotypes in published literature and tested at GeneDx; however, segregation data are limited at this time and this variant was also identified in control populations (Semmler et al., 2014; Lopes et al., 2015; Miszalski-Jamka et al., 2017); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 25208129, 28798025, 25617006) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LDB3: BP4, BS2 -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 22, 2014	Variant classified as Uncertain Significance - Favor Benign. The Ala222Thr varia nt in LDB3 has been identified by our laboratory in 1 Caucasian infant with HCM, 1 Caucasian young adult with unspecified cardiomyopathy, and 1 Caucasian adult with HCM. This variant has also been identified in 4/8600 of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs139922045). Computational prediction tools do not provide strong su pport for or against an impact to the protein. However, alanine (Ala) at positio n 222 is not conserved in evolution and the change to threonine (Thr) is present in several species (black flying fox, megabat, and lizard), suggesting that a c hange at this position may be tolerated. In summary, while the clinical signific ance of the Ala222Thr variant is uncertain, these data suggest that it is more l ikely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2022	Variant summary: LDB3 c.664G>A (p.Ala222Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 239460 control chromosomes, predominantly at a frequency of 0.00071 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 28.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.664G>A has been reported in the literature in individuals affected with sporadic inclusion body myositis, myofibrillar myopathy, left ventricular non-compaction, and pediatric primary cardiomyopathy; in the latter three cases a pathogenic variant in a different gene was reported in the patients which could explain their phenotype, supporting a benign role for LDB3 c.664G>A (Weihl_2015, Semmler_2014, Miszalski-Jamka_2017, Kuhnisch_2019). 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. Multiple laboratories reported the variant with conflicting assessments: four submitters classified the variant as VUS while three classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 25, 2019

- -

Myofibrillar myopathy 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

LDB3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

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). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

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

0.071

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;T;T;.;.

Eigen

Benign

0.026

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;.;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.057

T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.1

M;M;M;.;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

N;.;N;N;.;N

REVEL

Benign

0.095

Sift

Benign

0.24

T;.;T;D;.;D

Sift4G

Benign

0.37

T;T;T;T;T;T

Polyphen

0.0010, 0.19, 0.83

.;.;B;.;B;P

Vest4

0.24

MVP

0.72

MPC

0.20

ClinPred

0.068

GERP RS

3.7

Varity_R

0.11

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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