rs755513516
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001368067.1(LDB3):c.370C>A(p.Pro124Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P124L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001368067.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDB3 | NM_001368067.1 | c.370C>A | p.Pro124Thr | missense_variant | 6/9 | ENST00000263066.11 | |
LDB3 | NM_007078.3 | c.690-4802C>A | intron_variant | ENST00000361373.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000263066.11 | c.370C>A | p.Pro124Thr | missense_variant | 6/9 | 1 | NM_001368067.1 | ||
LDB3 | ENST00000361373.9 | c.690-4802C>A | intron_variant | 1 | NM_007078.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249378Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135300
GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461818Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 727196
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74498
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201860; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2020 | - - |
Dilated cardiomyopathy 1C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine. (I) 0219 - This variant is non-coding in alternative transcripts, including the predominantly reported in ClinVar, NM_007078.3, which has higher expression in heart tissues (GTEx). However, it is coding in other transcripts expressed in cardiac tissue (GTEx). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (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) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 124 of the LDB3 protein (p.Pro124Thr). This variant is present in population databases (rs755513516, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of LDB3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 201860). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 30, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at