10-86718772-G-C

Position:

• chr10-86718772-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007078.3(LDB3):​c.1903G>C​(p.Val635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V635I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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]

LDB3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_007078.3	c.1903G>C	p.Val635Leu	missense_variant	12/14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1903G>C	p.Val635Leu	missense_variant	12/14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myofibrillar myopathy 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with LDB3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 635 of the LDB3 protein (p.Val635Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. The LDB3 gene has multiple clinically relevant transcripts. The p.Val635Leu variant occurs in alternate transcript NM_007078.2, which corresponds to position c.*19398G>C in NM_001080116.1:, the primary transcript listed in the Methods. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;.;D;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.5	.;.;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;.;N;N;.
REVEL	Uncertain	0.57
Sift	Benign	0.039	D;.;T;T;.
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.43, 0.21	.;.;B;B;.
Vest4		0.65
MutPred		0.34		.;.;Loss of catalytic residue at V635 (P = 0.0366);.;.;
MVP		0.90
MPC		0.22
ClinPred		0.83	D
GERP RS		3.6
Varity_R		0.17
gMVP		0.33

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: rs45618633; hg19: chr10-88478529;