rs145983824

chr10-86718110-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PP3_Strong BS2

The NM_007078.3(LDB3):c.1823C>T(p.Pro608Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P608P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7
• Conservation: PhyloP100: 7.91

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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_007078.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1823C>T	p.Pro608Leu	missense_variant	11/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1823C>T	p.Pro608Leu	missense_variant	11/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251488 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135922

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000809

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:7

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	Aug 22, 2022	Variant summary: LDB3 c.1823C>T (p.Pro608Leu) results in a non-conservative amino acid change located in the zinc finger, LIM-type domain (IPR001781) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251488 control chromosomes (gnomAD). The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDB3 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant may be benign. c.1823C>T has been reported in the literature in settings of multigene panel testing in individuals affected with dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction (e.g. Theis_2006, Akinrinade_2015, Walsh_2017, Mazzarotto_2021, Shen_2022). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2014	The Pro608Leu variant in LDB3 has now been identified by our laboratory in 1 Cau casian adult with LVNC and biventricular enlargement, who also carried a likely pathogenic variant in another gene, and 1 Black adult with DCM (LMM unpublished data; including this individual). In addition, this variant has also been identi fied in 1/8600 European American chromosomes and in 2/4406 African American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/ ; dbSNP rs145983824). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may imp act the protein, though this information is not predictive enough to determine p athogenicity. Additional information is needed to fully assess the clinical sign ificance of the Pro608Leu variant. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	Reported as P615L in an adult male with HCM (Theis et al., 2006); Reported in ClinVar (ClinVar Variant ID# 45533; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28518168, 17097056) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2021	The LDB3 c.1823C>T; p.Pro608Leu variant (rs145983824), also known as c.*18736C>T for NM_001080116.1, is reported in the literature in an individual affected with hypertrophic cardiomyopathy (reported as Pro615Leu, Theis 2006). This variant is also reported in ClinVar (Variation ID: 45533), and is found in the general population with an overall allele frequency of 0.0074% (21/282888 alleles) in the Genome Aggregation Database. The proline at codon 608 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.759). However, given the lack of clinical and functional data, the significance of the p.Pro608Leu variant is uncertain at this time. References: Theis JL et al. Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2006 Dec 29;351(4):896-902. -

Familial hypertrophic cardiomyopathy 24 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 29, 2006

- -

Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 15, 2022

- -

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*18736C>T in the primary transcript. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 608 of the LDB3 protein (p.Pro608Leu). This variant is present in population databases (rs145983824, gnomAD 0.009%). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Jan 26, 2022

The p.P608L variant (also known as c.1823C>T), located in coding exon 10 of the LDB3 gene, results from a C to T substitution at nucleotide position 1823. The proline at codon 608 is replaced by leucine, an amino acid with similar properties. This variant (referred to as p.P615L) has been reported in an individual with hypertrophic cardiomyopathy (Theis JL et al. Biochem. Biophys. Res. Commun., 2006 Dec;351:896-902), and has also been reported in an exome cohort; however, clinical details were limited (Tang D et al. Sci Rep, 2018 Jul;8:10912). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.5	D;.;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.92
MVP		0.97
MPC		0.77
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.47

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: rs145983824; hg19: chr10-88477867; COSMIC: COSV53943358; COSMIC: COSV53943358;