10-86716702-T-C

Variant names:

• chr10-86716702-T-C
• rs727503128
• NM_007078.3:c.1607T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_007078.3(LDB3):​c.1607T>C​(p.Val536Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.54

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22048113).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_007078.3	c.1607T>C	p.Val536Ala	missense_variant	Exon 10 of 14	ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000361373.9	c.1607T>C	p.Val536Ala	missense_variant	Exon 10 of 14	1	NM_007078.3	ENSP00000355296.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461504 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Val536Ala varia nt in LDB3 has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to assess the frequency of th is variant. Valine (Val) at position 536 is not conserved in evolution and >10 f ish species carry an alanine (Ala), supporting that this change may be tolerated . Additional computational analyses (biochemical amino acid properties, AlignGVG D, PolyPhen2, and SIFT) do not provide strong support for or against an impact t o the protein. Although the presence of the variant amino acid in other species supports that this variant is more likely benign, additional studies are needed to fully assess the clinical significance of this variant. -

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

Sep 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myofibrillar myopathy 4 Uncertain:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with alanine at codon 536 of the LDB3 protein (p.Val536Ala). The valine residue is highly conserved and there is a small physicochemical difference between the two amino acids. The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.2, and corresponds to NM_001080116.1:c.*17328T>C in the primary transcript. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 536 of the LDB3 protein (p.Val536Ala). This variant is present in population databases (rs727503128, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LDB3-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T;.
Eigen	Benign	-0.083
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	.;.;L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N;.;N;N
REVEL	Benign	0.089
Sift	Benign	0.095	T;.;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.24, 0.0	.;.;B;B
Vest4		0.17
MutPred		0.29		.;.;Loss of helix (P = 0.0558);.;
MVP		0.81
MPC		0.25
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.38

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: rs727503128; hg19: chr10-88476459;