rs200596619

chr10-86681580-G-Achr10-86681580-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007078.3(LDB3):c.466G>A(p.Ala156Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,612,990 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A156V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 0.0360

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005451441).
• BP6: Variant 10-86681580-G-A is Benign according to our data. Variant chr10-86681580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 180399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86681580-G-A is described in Lovd as [Benign]. Variant chr10-86681580-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.466G>A	p.Ala156Thr	missense_variant	5/14	ENST00000361373.9
LDB3	NM_001368067.1	c.321+1423G>A		intron_variant		ENST00000263066.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.466G>A	p.Ala156Thr	missense_variant	5/14	1	NM_007078.3	P4
LDB3	ENST00000263066.11	c.321+1423G>A		intron_variant		1	NM_001368067.1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152170 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000836 AC: 207 AN: 247480 Hom.: 2 AF XY: 0.000878 AC XY: 118 AN XY: 134430

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.000342

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1460704 Hom.: 3 Cov.: 32 AF XY: 0.000391 AC XY: 284 AN XY: 726690

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00688

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152286 Hom.: 0 Cov.: 34 AF XY: 0.000900 AC XY: 67 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000381 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000643 AC: 78

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	LDB3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	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.Ala156Thr Based on the data reviewed below we consider this variant a variant of uncertain significance. LIM domain binding 3, also known as LDB3 or ZASP, is a protein which in humans is encoded by the LDB3 gene. Mutations in the LDB3 gene have been reported in patients with autosomal dominant familial dilated cardiomyopathy, however it is currently not known what percentage of individuals with familial DCM have a mutation in the LDB3 gene (Hershberger R et al., 2009). Variants in LDB3 have also been associated with Myofibrillar myopathy (MFM), a morphologically distinct disorder in which disintegration of the Z-disk and then of the myofibrils is followed by abnormal accumulation of multiple proteins. Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Matteo and colleagues studied 100 probands, 15 with identified LVNC. Creatinine kinase levels were normal in all the probands and there was no clinical evidence of a skeletal myopathy. Mutations in ZASP (LDB3) were identified in 6 of the 100 probands, four of whom with identified LVNC and two with DCM (Vatta, M et al., 2003) They did not test other genes associated with DCM and LVNC. No mutations were identified in 200 ethnically matched control individuals (400 chromosomes). Arimurat and colleagues studied ZASP/Cypher gene in 96 unrelated Japanese patients with dilated cardiomyopathy. Five variations were identified in codons -5, 55, 588, 626, 644. They determined V55I and V588I to be polymorphisms because they were also found in unrelated healthy controls. The D626N variation identified in a proband patient of familial DCM was not found in 400 unrelated healthy controls. This variant was shown to alter the function of the LIM domain. They described the phenotype of the family with this variant as having "late onset DCM"; after age 50. No clinical features of LVNC were indicated. Selcen and Engel, 2005 studied ZASP sequence variants in 54 patients with myofibrillar myopathy (MFM) and detected 3 heterozygous missense mutations in 11 patients. Most patients had proximal and distal weakness. Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk and one carried a missense mutation in exon 9 (R268C). The A147T variant segregated with disease in 3 additional affected family members. The A165V variant is within, and the A147T mutation is immediately before the ZM motif needed for interaction with actinin. The variants were not present in 220 alleles from control subjects. This variant Ala156Thr is novel and has not been reported as a disease-causing or as a benign polymorphism. The variant p.Ala156Thr is in exon 4 of the LDB3 gene (NM_007078.2) and is within the ZM motif needed for interaction with actinin. This is a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue. In silico analysis with PolyPhen-2 predicts the variant to be benign. Mutation Taster predicts this variant to be a polymorphism. The alanine at codon 156 is NOT conserved across species. Other variants have been reported in association with disease at nearby codons (Ala147Thr; Ala165Val). In total the variant has not been 710 published controls. Ala156Thr is seen in 4 of 8588 European alleles and 0 of 4400 African American alleles in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6,500 Caucasian and African American individuals (as of 7/7/13). This variant is listed in dbSNP (rs200596619). The variant was not observed in the following published contro -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 03, 2020	- -

Myofibrillar myopathy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Feb 24, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2018

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	0.067
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.8
Dann	Benign	0.72
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.60	T;.;T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0055	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N;N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.0	N;.;N;N;.;N
REVEL	Benign	0.036
Sift	Benign	0.59	T;.;T;T;.;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		0.0, 0.0080	.;.;B;.;B;B
Vest4		0.075
MVP		0.42
MPC		0.19
ClinPred		0.028	T
GERP RS		-0.66
Varity_R		0.022
gMVP		0.46

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: rs200596619; hg19: chr10-88441337;