10-86692566-G-C

Variant names:

• chr10-86692566-G-C
• rs374336814
• NM_007078.3:c.891G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007078.3(LDB3):​c.891G>C​(p.Arg297Ser) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000289258 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36347157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.891G>C	p.Arg297Ser	missense_variant	Exon 7 of 14	ENST00000361373.9	NP_009009.1
LDB3	NM_001368067.1	c.750G>C	p.Arg250Ser	missense_variant	Exon 8 of 9	ENST00000263066.11	NP_001354996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.891G>C	p.Arg297Ser	missense_variant	Exon 7 of 14	1	NM_007078.3	ENSP00000355296.3
LDB3	ENST00000263066.11	c.750G>C	p.Arg250Ser	missense_variant	Exon 8 of 9	1	NM_001368067.1	ENSP00000263066.7
ENSG00000289258	ENST00000443292.2	c.2400G>C	p.Arg800Ser	missense_variant	Exon 17 of 18	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.891G>C (p.R297S) alteration is located in exon 6 (coding exon 6) of the LDB3 gene. This alteration results from a G to C substitution at nucleotide position 891, causing the arginine (R) at amino acid position 297 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;.;.;D;.;.;.
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	.;.;.;M;M;.;.
PhyloP100		0.65
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D;.;D;D;.;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.011	D;.;D;D;.;D;D
Sift4G	Benign	0.15	T;T;D;D;D;D;D
Polyphen		0.99, 0.98, 1.0, 0.97, 0.95	.;.;D;D;D;D;P
Vest4		0.53
MutPred		0.25		.;.;.;Gain of phosphorylation at R297 (P = 0.0378);Gain of phosphorylation at R297 (P = 0.0378);.;.;
MVP		0.80
MPC		0.79
ClinPred		0.90	D
GERP RS		1.3
Varity_R		0.41
gMVP		0.37
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs374336814; hg19: chr10-88452323;