ClinVar Miner

Submissions for variant NM_007078.3(LDB3):c.1382A>C (p.Tyr461Ser)

gnomAD frequency: 0.00002  dbSNP: rs774224466
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001812301 SCV001470992 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing The c.1382A>C; p.Tyr461Ser variant (rs774224466) has been reported in one patient with hypertrophic cardiomyopathy, who also carried a frameshift mutation in the Z-disc gene CSRP3 (Thies 2006). This variant is found in the general population with an overall allele frequency of 0.003% (6/210,866 alleles) in the Genome Aggregation Database. The tyrosine at codon 461 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. This variant is found in an alternate transcript of LDB3 that is not highly expressed in heart muscle (Genotype-Tissue Expression project), however the association with cardiomyopathy is unknown. Given the lack of clinical and functional data, the significance of the p.Tyr461Ser variant is uncertain at this time.
Invitae RCV001871666 SCV002198773 uncertain significance Myofibrillar myopathy 4 2022-10-07 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is also known as Y468S. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 17097056). This variant is present in population databases (rs774224466, gnomAD 0.02%). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 461 of the LDB3 protein (p.Tyr461Ser). The LDB3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_007078.3, and corresponds to NM_001080116.1:c.*17103A>C in the primary transcript.
Ambry Genetics RCV002379976 SCV002696751 uncertain significance Cardiovascular phenotype 2022-07-21 criteria provided, single submitter clinical testing The p.Y461S variant (also known as c.1382A>C), located in coding exon 9 of the LDB3 gene, results from an A to C substitution at nucleotide position 1382. The tyrosine at codon 461 is replaced by serine, an amino acid with dissimilar properties. This alteration, which is also known as p.Y468S, has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Theis JL et al. Biochem Biophys Res Commun, 2006 Dec;351:896-902). This amino acid position is 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.

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