rs121908333

Positions:

• chr10-86687163-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. 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 (★★).

• 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:9 O:1
• Conservation: PhyloP100: 10.0

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]

ENSG00000289258 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• 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 [Likely_pathogenic]. Clinvar id is 4727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-86687163-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDB3	NM_001368067.1	c.439G>A	p.Ala147Thr	missense_variant	6/9	ENST00000263066.11	NP_001354996.1
LDB3	NM_007078.3	c.690-4733G>A		intron_variant		ENST00000361373.9	NP_009009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDB3	ENST00000263066.11	c.439G>A	p.Ala147Thr	missense_variant	6/9	1	NM_001368067.1	ENSP00000263066.7
LDB3	ENST00000361373.9	c.690-4733G>A		intron_variant		1	NM_007078.3	ENSP00000355296.3
ENSG00000289258	ENST00000443292.2	c.2199-4733G>A		intron_variant		1		ENSP00000393132.2

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

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 147 of the LDB3 protein (p.Ala147Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myofibrillar myopathy (PMID: 15668942, 23263837). ClinVar contains an entry for this variant (Variation ID: 4727). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects LDB3 function (PMID: 24668811). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 10, 2021	This sequence change is predicted to replace alanine with threonine at codon 147 of the LDB3 protein (p.(Ala147Thr), also known as NM_007078.2:c.690-4733G>A). The alanine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the striated muscle ZASP-like motif in exon 6 of the skeletal muscle isoform (PMID: 28349680). There is a small physicochemical difference between alanine and threonine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in multiple individuals with myofibrillar myopathy, including variable cardiac and neuropathic involvement, and segregates with disease in at least one large family (PMID: 15668942, 18765652, 21676617, 23263837, 32721234). The variant demonstrates isoform-specific disruption of skeletal muscle actin filaments in functional assays (PMID: 24668811). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/4 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PP1_Moderate, PS3_Supporting, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is the proposed mechanism of disease in this gene and is associated with myofibrillar myopathy 4 (MIM#609452). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with myofibrillar myopathy (ClinVar, PMID: 18055494). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	LDB3: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 31, 2024	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with myofibrillar myopathy and appears to segregate with disease in at least one family. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	Published functional studies demonstrate disruption of the actin cytoskeleton in mouse muscle cells (Lin et. al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16427346, 32721234, 23263837, 15668942, 24668811, 18765652, no PMID, 19377068, 27546599, 28349680, 21676617) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2023	- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 25, 2024

This variant has also been referred to as p.Ala147Thr using alternate transcripts, and reported using the historical gene name, ZASP. The c.690-4733G nucleotide is highly conserved. It has not been reported in control populations in the Genome Aggregation Database (gnomAD). It has been previously reported in at >5 apparently unrelated individuals with myofibrillar myopathy (MFM) (PMID 15668942, 18765652, 23263837, 21676617) and is considered to be one of the most common MFM-related LDB3 variants (PMID 33802723). This variant was reported to segregate with disease in 1 family (PMID 15668942). 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). However, another functional study demonstrated that this variant does not impact binding to phosphoglucomutase I, which is thought to be the mechanism of LDB3 involvement in dilated cardiomyopathy (PMID 19377068). In silico splicing analyses do not predict the c.690-4733G>A variant to have a significant effect on splicing. However, this prediction has not been confirmed by RNA functional studies. This variant is listed in ClinVar (VCV000004727). Based on the above evidence, we classify this variant as likely pathogenic for myofibrillar myopathy, which, in rare cases, could also produce cardiomyopathy. -

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

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 05-08-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;.;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
PROVEAN	Benign	-1.2	N;.;N;N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.019	D;.;T;D;D
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.065, 1.0, 1.0	.;.;B;D;D
Vest4		0.75
MutPred		0.46		.;.;Gain of ubiquitination at K146 (P = 0.0762);.;Gain of ubiquitination at K146 (P = 0.0762);
MVP		0.87
MPC		0.72
ClinPred		0.93	D
GERP RS		5.0
gMVP		0.92

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: rs121908333; hg19: chr10-88446920;