NM_001368067.1:c.439G>A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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
Consequence
NM_001368067.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000263066.11 | c.439G>A | p.Ala147Thr | missense_variant | Exon 6 of 9 | 1 | NM_001368067.1 | ENSP00000263066.7 | ||
LDB3 | ENST00000361373.9 | c.690-4733G>A | intron_variant | Intron 5 of 13 | 1 | NM_007078.3 | ENSP00000355296.3 | |||
ENSG00000289258 | ENST00000443292.2 | c.2199-4733G>A | intron_variant | Intron 15 of 17 | 1 | ENSP00000393132.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Myofibrillar myopathy 4 Pathogenic:4
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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. -
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 -
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. -
not provided Pathogenic:4
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) -
LDB3: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting -
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. -
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Dilated cardiomyopathy 1C;C4721886:Myofibrillar myopathy 4 Pathogenic:1Other:1
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. -
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Cardiomyopathy Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at