rs530979771

Positions:

chr10-86681770-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The ENST00000361373.9(LDB3):c.656G>A(p.Arg219Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,600,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

LDB3
ENST00000361373.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.37

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 Likely_benign. Variant got -4 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity LDB3_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.087856084).

BS2

High AC in GnomAdExome4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3 linkuse as main transcript	c.656G>A	p.Arg219Gln	missense_variant	5/14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1 linkuse as main transcript	c.321+1613G>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.656G>A	p.Arg219Gln	missense_variant	5/14	1	NM_007078.3	ENSP00000355296	P4	O75112-1
LDB3	ENST00000263066.11 linkuse as main transcript	c.321+1613G>A		intron_variant		1	NM_001368067.1	ENSP00000263066		O75112-6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000414

AC:

AN:

241616

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

130604

show subpopulations

Gnomad AFR exome

AF:

0.000125

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:

0.0000474

Gnomad NFE exome

AF:

0.0000636

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

1447740

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

718230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000543

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

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:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2024	Variant summary: LDB3 c.656G>A (p.Arg219Gln) results in a conservative amino acid change located in the PDZ and LIM domain protein 1-4/Zasp-like, middle domain (IPR031847) 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 4.1e-05 in 241616 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDB3 causing Hypertrophic Cardiomyopathy (4.1e-05 vs 7.5e-05), allowing no conclusion about variant significance. c.656G>A has been reported in the literature in the heterozgous state in at least one individual affected with restrictive cardiomyopathy who also carreid a variant in MYH7 (Kistareva_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27662471). ClinVar contains an entry for this variant (Variation ID: 179653). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2014	The Arg219Gln variant in LDB3 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that the Arg219Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogeni city. Additional information is needed to fully assess the clinical significance of the Arg219Gln variant. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2020	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179653; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 30, 2017	p.Arg219Gln (R219Q; c.656G>A) in exon 4 of the LDB3 gene (alternative transcript NM_001171610.1) Chromosome position 10:88441527 G / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It does not look particularly suspicious to cause disease, given that it has not been convincingly reported to cause disease in a patient, and also given how variable this codon is across species. This variant has not previously been reported in the literature in association with disease. It is present in population databases. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Glutamine. Arginine at this location is poorly conserved across ~100 vertebrate species for which we have data. It is frequently replaced by a positively-charged Lysine or a polar Asparagine, among other amino acids. Adjacent amino acids are also poorly conserved. There are no convincingly Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). This variant was reported in 7 individuals with European ancestry in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 6 non-Finnish Europeans (for the highest minor allele frequency: 0.006%), and 1 Finnish European. Overall MAF = 0.003%. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Myofibrillar myopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.321+1613G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 219 of the LDB3 protein (p.Arg219Gln). This variant is present in population databases (rs530979771, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179653). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2018

The p.R219Q variant (also known as c.656G>A), located in coding exon 4 of the LDB3 gene, results from a G to A substitution at nucleotide position 656. The arginine at codon 219 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in an individual with idiopathic restrictive cardiomyopathy, who also had additional cardiac variants detected (Kostareva A et al. PLoS ONE Sep;11:e0163362). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;T;T;.;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.0063

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

D;.;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.088

T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.4

L;L;L;.;L;L

MutationTaster

Benign

0.59

D;D;D;D;D;D;D;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

N;.;N;N;.;N

REVEL

Benign

0.081

Sift

Benign

0.27

T;.;T;T;.;T

Sift4G

Benign

0.14

T;T;T;T;T;T

Polyphen

0.059, 0.038, 0.96

.;.;B;.;B;D

Vest4

0.27

MVP

0.67

MPC

0.55

ClinPred

0.47

GERP RS

4.8

Varity_R

0.060

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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