10-86716384-C-T

Variant names:

• chr10-86716384-C-T
• rs746183666
• NM_007078.3:c.1289C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_007078.3(LDB3):​c.1289C>T​(p.Thr430Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000838 in 143,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. T430S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000084 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDB3 NM_007078.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.765
• Publications: 2 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12714449).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000838 (12/143156) while in subpopulation AFR AF = 0.000314 (12/38174). AF 95% confidence interval is 0.000181. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	NM_007078.3	MANE Select	c.1289C>T	p.Thr430Ile	missense	Exon 10 of 14	NP_009009.1
	LDB3	NM_001171610.2		c.1304C>T	p.Thr435Ile	missense	Exon 10 of 14	NP_001165081.1
	LDB3	NM_001368066.1		c.1148C>T	p.Thr383Ile	missense	Exon 11 of 15	NP_001354995.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.1289C>T	p.Thr430Ile	missense	Exon 10 of 14	ENSP00000355296.3
	LDB3	ENST00000623056.4	TSL:5	c.1304C>T	p.Thr435Ile	missense	Exon 10 of 14	ENSP00000485500.1
	LDB3	ENST00000689740.1		c.1148C>T	p.Thr383Ile	missense	Exon 11 of 15	ENSP00000510300.1

Frequencies

GnomAD3 genomes AF: 0.0000769 AC: 11 AN: 143062 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 4 AN: 242976 AF XY: 0.0000151

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000275 AC: 4 AN: 1454868 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 723564

African (AFR) AF: 0.000120 AC: 4 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 85620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109036

Other (OTH) AF: 0.00 AC: 0 AN: 60010

GnomAD4 genome AF: 0.0000838 AC: 12 AN: 143156 Hom.: 0 Cov.: 28 AF XY: 0.000101 AC XY: 7 AN XY: 69262

African (AFR) AF: 0.000314 AC: 12 AN: 38174

American (AMR) AF: 0.00 AC: 0 AN: 14102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4848

South Asian (SAS) AF: 0.00 AC: 0 AN: 4272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65658

Other (OTH) AF: 0.00 AC: 0 AN: 1980

Alfa AF: 0.0000662 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 4 Uncertain:1

Sep 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17010C>T in the primary transcript. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 430 of the LDB3 protein (p.Thr430Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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.

not provided Uncertain:1

Feb 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported using an alternate transcript of the gene; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function

Cardiovascular phenotype Uncertain:1

Jul 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1289C>T (p.T430I) alteration is located in exon 9 (coding exon 9) of the LDB3 gene. This alteration results from a C to T substitution at nucleotide position 1289, causing the threonine (T) at amino acid position 430 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.77
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.055
Sift	Benign	0.13	T
Sift4G	Benign	0.20	T
Polyphen		0.90	P
Vest4		0.37
MVP		0.75
MPC		0.30
ClinPred		0.27	T
GERP RS		2.3
Varity_R		0.096
gMVP		0.33
Mutation Taster		=82/18	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: rs746183666; hg19: chr10-88476141;