10-86716566-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007078.3(LDB3):c.1471G>T(p.Val491Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V491E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.71

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3099084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_007078.3	c.1471G>T	p.Val491Leu	missense_variant	10/14	ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000361373.9	c.1471G>T	p.Val491Leu	missense_variant	10/14	1	NM_007078.3	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2010

The Val491Leu variant has not been reported in the literature. Valine (Val) at position 491 is conserved across mammals, indicating that the change observed in this individual may not be tolerated. -

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This missense change has been observed in individual(s) with clinical features of LDB3-related conditions (PMID: 33500567). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 491 of the LDB3 protein (p.Val491Leu). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17192G>T in the primary transcript. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.032
Eigen_PC	Benign	0.042
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T;.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.023	D;.;D;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.78, 0.0020	.;.;P;B
Vest4		0.44
MutPred		0.13		.;.;Gain of glycosylation at P489 (P = 0.0953);.;
MVP		0.76
MPC		0.65
ClinPred		0.91	D
GERP RS		4.3
Varity_R		0.084
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs397517215; hg19: chr10-88476323;