Submissions for variant NM_007078.3(LDB3):c.1153A>G (p.Ser385Gly)

gnomAD frequency: 0.00001  dbSNP: rs777547764

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219802	SCV000271908	uncertain significance	not specified	2015-10-01	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ser385Gly var iant in LDB3 has not been previously reported in individuals with cardiomyopathy , but has been identified in 1/63978 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org). Serine (Ser) at position 3 85 is not conserved in mammals or evolutionarily distant species and 9 species, including 3 mammals (Elephant, Elephant Shrew, Cape Golden Mole) carry a glycine (Gly) at this position, raising the possibility that this change may be tolerat ed. In summary, while the clinical significance of the p.Ser385Gly variant is un certain, these data suggest that it is more likely to be benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000219802	SCV000740597	uncertain significance	not specified	2017-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV001247702	SCV001421140	uncertain significance	Myofibrillar myopathy 4	2023-07-26	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with LDB3-related conditions. This variant is present in population databases (rs777547764, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 385 of the LDB3 protein (p.Ser385Gly). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*10598A>G in the primary transcript.
Ambry Genetics	RCV002347843	SCV002622177	uncertain significance	Cardiovascular phenotype	2022-03-31	criteria provided, single submitter	clinical testing	The p.S385G variant (also known as c.1153A>G), located in coding exon 8 of the LDB3 gene, results from an A to G substitution at nucleotide position 1153. The serine at codon 385 is replaced by glycine, an amino acid with 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	RCV002478769	SCV002787342	uncertain significance	Dilated cardiomyopathy 1C; Myofibrillar myopathy 4	2021-07-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219802	SCV004021066	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: LDB3 c.1153A>G (p.Ser385Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248778 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1153A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.