NM_001368067.1:c.494C>T

Variant names:

• chr10-86687218-C-T
• rs121908334
• NM_001368067.1:c.494C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_001368067.1(LDB3):​c.494C>T​(p.Ala165Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000965091: Experimental studies have shown that this missense change affects LDB3 function (PMID:24647531, 24668811)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDB3 NM_001368067.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.91
• Publications: 19 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):

• dilated cardiomyopathy

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: ClinGen
• myofibrillar myopathy 4

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000965091: Experimental studies have shown that this missense change affects LDB3 function (PMID: 24647531, 24668811).; SCV002038571: "In functional studies using a mouse model or cells derived from mice, the phenotype observed in humans was recapitulated when the p.Ala165Val variant was present in a heterozygous state. This included presence of muscle weakness, characteristic muscle fiber structural abnormalities, protein aggregation patterns, and Z-disc disruption generally observed in myofibrillar myopathy (Lin et al. 2014; Pathak et al. 2014)."; SCV000060502: An in vitro function study showed that this variant disrupted Ankrd2 binding (Martinelli 2014) and a study of mouse myoblasts transfected with the p.Ala165Val mutation showed a disrution of Z-disc structure and an accumulation of F-actin (Lin 2014).; SCV000582060: Published functional studies demonstrate a damaging effect: Z-disc disruption and F-actin accumulation in mouse skeletal muscle, and disruption in the actin cytoskeleton in muscle cells (Lin et al., 2014); SCV000900654: "Functional studies have shown conflicting results: one reported that this variant did not impact the binding between LDB3 and phosphoglucomutase 1, which is suspected to be the mechanism of development of DCM (PMID 19377068), and others showed that this variant disrupted the actin cytoskeleton of muscle cells, as well as the Ankrd2 binding (which creates the link between the sarcomere and the nucleus in skeletal muscle) (PMID 24668811, PMID 24647531)."; SCV004747584: "In vitro and in vivo experimental studies suggest this variant impacts protein function (Lin et al. 2014. PubMed ID: 24668811; Martinelli et al. 2014. PubMed ID: 24647531; Pathak et al. 2021. PubMed ID: 33742095)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766
• PP5: Variant 10-86687218-C-T is Pathogenic according to our data. Variant chr10-86687218-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368067.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	NM_001368067.1	MANE Plus Clinical	c.494C>T	p.Ala165Val	missense	Exon 6 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_007078.3	MANE Select	c.690-4678C>T		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.839C>T	p.Ala280Val	missense	Exon 6 of 14	NP_001165081.1	O75112-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000263066.11	TSL:1 MANE Plus Clinical	c.494C>T	p.Ala165Val	missense	Exon 6 of 9	ENSP00000263066.7	O75112-6
	LDB3	ENST00000372056.8	TSL:1	c.839C>T	p.Ala280Val	missense	Exon 5 of 8	ENSP00000361126.4	O75112-4
	LDB3	ENST00000372066.8	TSL:1	c.494C>T	p.Ala165Val	missense	Exon 5 of 8	ENSP00000361136.3	O75112-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249596 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000494 Hom.: 0

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Myofibrillar myopathy 4 (3)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1C (1)
1	-	-	LDB3-related disorder (1)
1	-	-	Myofibrillar myopathy (1)
1	-	-	Neuromuscular disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.49	D
PhyloP100		7.9
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.78
Sift	Benign	0.35	T
Sift4G	Benign	0.17	T
Polyphen		0.72	P
Vest4		0.91
MutPred		0.51		Loss of catalytic residue at M160 (P = 0.0532)
MVP		0.89
MPC		0.76
ClinPred		0.91	D
GERP RS		5.1
gMVP		0.92
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs121908334; hg19: chr10-88446975; COSMIC: COSV105837287;