rs121908334

chr10-86687218-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LDB3 NM_001368067.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 ACMG points.

• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4728.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=10, Uncertain_significance=1}. Variant chr10-86687218-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB3	NM_001368067.1	c.494C>T	p.Ala165Val	missense_variant	6/9	ENST00000263066.11
LDB3	NM_007078.3	c.690-4678C>T		intron_variant		ENST00000361373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB3	ENST00000263066.11	c.494C>T	p.Ala165Val	missense_variant	6/9	1	NM_001368067.1
LDB3	ENST00000361373.9	c.690-4678C>T		intron_variant		1	NM_007078.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249596 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135402

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 SAS 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

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	LDB3: PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2022	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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28269794, 19377068, 27546599, 27618136, 25208129, 27638134, 18765652, 15668942, 33742095, 31791368, 21676617, 32419263, 31589614, 17337483, 24668811) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 09, 2014	- -

Myofibrillar myopathy 4 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 07, 2021	The LDB3 c.494C>T (p.Ala165Val) variant, also referred to as c.690-4678C>T, is a missense variant that has been reported in at least seven unrelated individuals with myofibrillar myopathy presenting with progressive muscle weakness, mainly distally, and myopathic motor unit potentials noted through electromyography. Muscle atrophy, tripping episodes, walking difficulty, peripheral neuropathy, decreased reflexes in the legs, tingling and numbness in the feet, and ankle movement problems were also noted in some individuals (Selcen and Engler 2005; Griggs et al. 2007; Fischer et al. 2008; Semmler et al. 2014). Only one individual had cardiac problems presenting as prolonged QT (Selec and Engler 2005). The p.Ala165Val variant segregated with disease in a large pedigree where six affected individuals carried the variant. Three additional family members who carried the variant were asymptomatic at the time of the study, but they ranged in age from 39-49 years (Griggs et al. 2007). 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). The p.Ala165Val variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Ala165Val variant is classified as pathogenic for myofibrillar myopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 165 of the LDB3 protein (p.Ala165Val). This variant is present in population databases (rs121908334, gnomAD 0.0009%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15668942, 25208129). ClinVar contains an entry for this variant (Variation ID: 4728). 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: 24647531, 24668811). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1C Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Neuromuscular disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 21, 2018

The p.Ala165Val variant in LDB3 has been reported in at least 6 individuals with myofibrillar myopathy and segregated with disease in 9 affected individuals fro m 1 family (Selcen 2005, Griggs 2007, Fischer 2008, Vincent 2016, LMM data). It has also been identified in 1/113280 of European chromosomes by gnomAD (http://g nomad.broadinstitute.org) and reported in ClinVar (Variant ID #4728). An in vitr o function study showed that this variant disrupted Ankrd2 binding (Martinelli 2 014) and a study of mouse myoblasts transfected with the p.Ala165Val mutation sh owed a disrution of Z-disc structure and an accumulation of F-actin (Lin 2014). In summary, this variant meets criteria to be classified as pathogenic for autos omal dominant myofibrillar myopathy. ACMG/AMP criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate. -

Myofibrillar myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Aug 16, 2016

- -

LDB3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The LDB3 c.494C>T variant is predicted to result in the amino acid substitution p.Ala165Val. This variant has been reported in individuals with myofibrillar myopathy and shown to segregate with disease in families (see, for example, Selcen and Engel. 2005. PubMed ID: 15668942; Griggs et al. 2007. PubMed ID: 17337483; Semmler et al. 2014. PubMed ID: 25208129). 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). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in a large population database. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.690-4678C>T intronic pathogenic mutation results from a C to T substitution 4678 nucleotides upstream from coding exon 5 in the LDB3 gene. This alteration, also known as c.494C>T p.A165V in isoform NM_001080116, has been detected in multiple individuals with myofibrillar myopathy and has been reported to segregate with disease (Selcen D et al. Ann. Neurol., 2005 Feb;57:269-76; Griggs R et al. Brain, 2007 Jun;130:1477-84; Olivé M et al. Neuromuscul. Disord., 2011 Aug;21:533-42; Semmler AL et al. Orphanet J Rare Dis, 2014 Aug;9:121; Vincent AE et al. Neuromuscul. Disord., 2016 10;26:691-701). Haplotype analysis has demonstrated that this variant is a European founder mutation (Griggs R et al. Brain, 2007 Jun;130:1477-84). Functional analyses indicate that this alteration may impact protein function, but the physiological relevance of the observed impacts is unclear (Lin X et al. J. Biol. Chem., 2014 May;289:13615-26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 23, 2020

- -

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	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Pathogenic	0.78
Sift	Benign	0.35	T;.;T;T;D
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.72, 1.0, 1.0	.;.;P;D;D
Vest4		0.91
MutPred		0.51		.;.;Loss of catalytic residue at M160 (P = 0.0532);.;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

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