rs141569007
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_007078.3(LDB3):c.1910C>T(p.Ala637Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A637A) has been classified as Likely benign.
Frequency
Consequence
NM_007078.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDB3 | NM_007078.3 | c.1910C>T | p.Ala637Val | missense_variant | 12/14 | ENST00000361373.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDB3 | ENST00000361373.9 | c.1910C>T | p.Ala637Val | missense_variant | 12/14 | 1 | NM_007078.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251422Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135890
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727236
GnomAD4 genome AF: 0.000164 AC: 25AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74302
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 31, 2013 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LDB3 p.Ala637Val Given the lack of case data, we consider this a variant of uncertain significance. We could find no reports of the variant in association with disease. In silico analysis predicts the variant to be probably damaging, per the GeneDx report. The alanine at codon 637 is conserved across species. The variant was reported online in 8 of 60,661 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 17th, 2015). Specifically, the variant was observed in 4 of 5,197 Africans, 2/8255 South Asians, 1/5,789 Latinos, 1/33,336 Europeans. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 18, 2008 | - - |
Myofibrillar myopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*19405C>T in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 637 of the LDB3 protein (p.Ala637Val). This variant is present in population databases (rs141569007, gnomAD 0.05%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 45536). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2022 | The p.A637V variant (also known as c.1910C>T), located in coding exon 11 of the LDB3 gene, results from a C to T substitution at nucleotide position 1910. The alanine at codon 637 is replaced by valine, an amino acid with similar properties. This variant has been reported in an individual with dilated cardiomyopathy (Pugh et al. Genet Med. 2014;16(8):601-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2019 | This variant is associated with the following publications: (PMID: 27532257, 24503780) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at