rs727503129

Positions:

• chr10-86716702-TC-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_007078.3(LDB3):​c.1609del​(p.Gln537ArgfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDB3 NM_007078.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 0.0230

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1609del	p.Gln537ArgfsTer28	frameshift_variant	10/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1609del	p.Gln537ArgfsTer28	frameshift_variant	10/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151974 Hom.: 0 Cov.: 31

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461504 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151974 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74224

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

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	Jan 30, 2023	Variant summary: LDB3 c.1609delC (p.Gln537ArgfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 2.7e-05 in 150748 control chromosomes (gnomAD v3.1). To our knowledge, no occurrence of c.1609delC in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. In ClinVar, all nonsense or truncation variants are classified as uncertain significance, including truncations upstream and downstream of this position. Additionally, the LDB3 gene is classified as "limited association" with dilated cardiomyopathy and "disputed association" with arrhythmogenic right ventricular cardiomyopathy by ClinGen. Therefore, currently available evidence does not support that loss-of-function variants are pathogenic for Cardiomyopathy. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=1), or VUS (n=2). 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	Oct 18, 2013	Variant classified as Uncertain Significance - Favor Pathogenic. The Gln537fs va riant in LDB3 has not been previously reported in any other families with cardio myopathy or in large European American or African American cohorts. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 537 and lead to a premature termination codon 28 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein (l oss of function). Studies in mice have shown that the spectrum of phenotypes res ulting from homozygous loss of function of LDB3 includes DCM (Zheng 2009; heart specific loss of function) and congenital myopathy (Zhou 2001, complete loss of function). Our laboratory has previously identified one loss of function varian t in an individual with VT and SCA but overall, this type of variant has not yet been reported in individuals with cardio/myopathy. In summary, the predicted im pact to the protein increases the likelihood that this variant is pathogenic but additional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 19, 2016

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 26, 2017

- -

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2020

This sequence change creates a premature translational stop signal (p.Gln537Argfs*28) in the LDB3 gene. It is expected to result in an absent or disrupted protein product. The LDB3 gene has multiple clinically relevant transcripts. The p.Gln537Argfs*28 variant occurs in alternate transcript NM_007078.2, which corresponds to c.*17330del in NM_001080116.1, the primary transcript listed in the Methods. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 163850). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LDB3 cause disease. 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

Apr 07, 2023

The c.1609delC variant, located in coding exon 9 of the LDB3 gene, results from a deletion of one nucleotide at nucleotide position 1609, causing a translational frameshift with a predicted alternate stop codon (p.Q537Rfs*28). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of LDB3 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs727503129; hg19: chr10-88476459;