rs45521338

Positions:

• chr10-86691999-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_007078.3(LDB3):​c.793C>T​(p.Arg265Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 3.89

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07022998).
• BP6: Variant 10-86691999-C-T is Benign according to our data. Variant chr10-86691999-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45555.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.793C>T	p.Arg265Cys	missense_variant	6/14	ENST00000361373.9
LDB3	NM_001368067.1	c.652C>T	p.Arg218Cys	missense_variant	7/9	ENST00000263066.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.793C>T	p.Arg265Cys	missense_variant	6/14	1	NM_007078.3	P4
LDB3	ENST00000263066.11	c.652C>T	p.Arg218Cys	missense_variant	7/9	1	NM_001368067.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251420 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74474

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23861362, 20474083, 28821295) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 18, 2022	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 03, 2012	The Arg265Cys variant in LDB3 has been identified in 0.5% (2/394) of Chinese chr omosomes from a broad population by the 1000 Genomes Project (dbSNP rs45521338) and in 1/4406 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Although detection of this variant in these populations raises the possibility that this variant ma y be benign, it cannot be ruled out that these individuals are not presymptomati c. Computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. Addit ional information is needed to fully assess the clinical significance of this va riant. -
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.793C>T (p.Arg265Cys) results in a non-conservative amino acid change located in the PDZ and LIM domain protein 1-4/Zasp-like, middle domain (IPR031847) of 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 0.00015 in 251420 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33-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 East Asian origin. c.793C>T has been reported in the literature in an Asian male affected with congenital left ventricular aneurysm and prominent left ventricular trabeculation (e.g. Shan_2017), in a Chinese individual affected with dilated cardiomyopathy (e.g. Shen_2022), and in a participant from a exome sequencing cohort not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (e.g. Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23861362, 28821295, 35284542). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=1) or uncertain sinificance (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Dilated cardiomyopathy 1C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is the proposed mechanism of disease in this gene associated with missense variants and is associated with dilated cardiomyopathy 1C, with or without LVNC (MIM#601493), hypertrophic cardiomyopathy 24 (MIM#601493), left ventricular noncompaction 3 (MIM#601493) and myofibrillar myopathy 4 (MIM#609452) (PMID: 19377068). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (37 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (36 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DUF4749 domain (NCBI). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change to a histidine has conflicting reports of likely benign and VUS in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely pathogenic in an individual with congenital left ventricular aneurysm and prominent left ventricular trabeculation (PMID: 28821295). It is also reported as VUS in another individual with cardiomyopathy (PMID: 23861362). In addition, conflicting reports of likely benign and VUS are listed 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 -

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the LDB3 protein (p.Arg218Cys). This variant is present in population databases (rs45521338, gnomAD 0.08%). This missense change has been observed in individual(s) with congentital left ventricular aneurysm and left ventricular trabeculation (PMID: 28821295). This variant is also known as c.793C>T, p.Arg265Cys. ClinVar contains an entry for this variant (Variation ID: 45555). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 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	0.22
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	.;.;.;D;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.070	T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	.;.;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;.;D;D;.;D;D
REVEL	Benign	0.24
Sift	Benign	0.057	T;.;D;D;.;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		0.58, 0.48, 0.55, 0.62, 0.25	.;.;P;P;P;P;B
Vest4		0.52
MVP		0.81
MPC		0.48
ClinPred		0.25	T
GERP RS		5.9
Varity_R		0.22
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs45521338; hg19: chr10-88451756; COSMIC: COSV99555957;