Submissions for variant NM_007078.3(LDB3):c.818G>A (p.Arg273His)

gnomAD frequency: 0.00002  dbSNP: rs763481542

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001108264	SCV001265485	uncertain significance	Myofibrillar myopathy 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001108265	SCV001265486	uncertain significance	Dilated cardiomyopathy 1C	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001108264	SCV001385418	uncertain significance	Myofibrillar myopathy 4	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 226 of the LDB3 protein (p.Arg226His). This variant is present in population databases (rs763481542, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). This variant is also known as NM_001171611:c.1022G>A (p.Arg341His). ClinVar contains an entry for this variant (Variation ID: 880174). 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 disruptive. 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.
Ambry Genetics	RCV002429758	SCV002679656	uncertain significance	Cardiovascular phenotype	2022-08-25	criteria provided, single submitter	clinical testing	The p.R273H variant (also known as c.818G>A), located in coding exon 5 of the LDB3 gene, results from a G to A substitution at nucleotide position 818. This variant (described as p.R341H) was detected in a dilated cardiomyopathy cohort; however, clinical details were limited (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a). The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002489756	SCV002775453	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-08-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480959	SCV004225284	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing