rs121908333

Variant names:

• chr10-86687163-G-A
• rs121908333
• NM_001368067.1:c.439G>A
• LDB3 p.Ala147Thr

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_001368067.1(LDB3):​c.439G>A​(p.Ala147Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000545674: Experimental studies have shown that this missense change affects LDB3 function (PMID:24668811)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A147G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDB3 NM_001368067.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: 10.0
• Publications: 10 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000545674: Experimental studies have shown that this missense change affects LDB3 function (PMID: 24668811).; SCV002498642: The variant demonstrates isoform-specific disruption of skeletal muscle actin filaments in functional assays (PMID: 24668811).; SCV000322056: Published functional studies demonstrate disruption of the actin cytoskeleton in mouse muscle cells (Lin et. al., 2014); SCV000901575: Functional studies showed conflicting results for this variant. One study demonstrated significant biological impact for this variant in relation to myofibrillar myopathy: this variant disrupted the actin cytoskeleton in transfected mouse muscle cells (PMID 24668811).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-86687163-G-A is Pathogenic according to our data. Variant chr10-86687163-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4727.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.439G>A	p.Ala147Thr	missense	Exon 6 of 9	NP_001354996.1	A0A0S2Z530
	LDB3	NM_007078.3	MANE Select	c.690-4733G>A		intron	N/A	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.784G>A	p.Ala262Thr	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.439G>A	p.Ala147Thr	missense	Exon 6 of 9	ENSP00000263066.7	O75112-6
	LDB3	ENST00000372056.8	TSL:1	c.784G>A	p.Ala262Thr	missense	Exon 5 of 8	ENSP00000361126.4	O75112-4
	LDB3	ENST00000372066.8	TSL:1	c.439G>A	p.Ala147Thr	missense	Exon 5 of 8	ENSP00000361136.3	O75112-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Myofibrillar myopathy 4 (4)
1	-	-	Cardiomyopathy (1)
1	-	-	Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Pathogenic	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.46	D
PhyloP100		10
PROVEAN	Benign	-1.2	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.019	D
Sift4G	Benign	0.53	T
gMVP		0.92
Mutation Taster		=1/99	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121908333;

hg19: chr10-88446920;