ClinVar Miner

Submissions for variant NM_014391.2(ANKRD1):c.313C>T (p.Pro105Ser) (rs148189486)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172517 SCV000050887 likely benign Primary dilated cardiomyopathy 2013-06-24 criteria provided, single submitter research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725419 SCV000336823 uncertain significance not provided 2015-11-04 criteria provided, single submitter clinical testing
GeneDx RCV000725419 SCV000520827 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing The P105S variant of uncertain significance in the ANKRD1 gene has been previously reported in two Caucasian individuals in association with DCM (Moulik et al., 2009). One individual presented at 15 years of age and who had a father with isolated left ventricular dilation, and another individual presented at 52 years of age but had no known family history of DCM; however, segregation studies were not described for either individual (Moulik et al., 2009). This variant is observed in 40/125,982 alleles (0.03%) from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Additionally, P105S was reported in 2/1736 (0.11%) alleles from a cohort of individuals not selected for cardiomyopathy, arrhythmia or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013), although follow-up cardiac evaluations were not reported.The P105S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies using the yeast two-hybrid assay showed that P105S disrupts ANKRD1 protein binding with the cardiac muscle cell adhesion protein, TALIN-1 (Moulik et al., 2009). Moulik et al. (2009) also showed that P105S did not disrupt the intracellular localization of ANKRD1 protein when expressed in cultured cells, but during mechanical stretch, P105S caused the down-regulation of P53 protein and up-regulation of MYOGENIN protein compared to wild-type ANKRD1 protein, suggesting a gain-of function-effect as a transcription cofactor. However, how these binding and cell culture studies translate to the role of P105S in human disease remains to be determined. Furthermore, this variant has not been identified in a significant number of affected individuals, and there is no segregation data available to further clarify the role of this variant in disease.
Ambry Genetics RCV000622147 SCV000736424 uncertain significance Cardiovascular phenotype 2018-08-31 criteria provided, single submitter clinical testing The p.P105S variant (also known as c.313C>T), located in coding exon 3 of the ANKRD1 gene, results from a C to T substitution at nucleotide position 313. The proline at codon 105 is replaced by serine, an amino acid with similar properties. This alteration was described in individuals with dilated cardiomyopathy but no segregation information was available (Moulik M et al. J. Am. Coll. Cardiol., 2009 Jul;54:325-33). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This alteration was reported to disrupt Talin-1 binding in yeast two hybrid system. In addition, the same study also found that during mechanical stretch, this alteration would decrease P53 expression while increasing myogenin expression (Moulik M et al. J. Am. Coll. Cardiol., 2009 Jul;54:325-33). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other 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.
Invitae RCV000690391 SCV000818075 uncertain significance ANKRD1-related dilated cardiomyopathy 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 105 of the ANKRD1 protein (p.Pro105Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs148189486, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19608030). ClinVar contains an entry for this variant (Variation ID: 192112). Experimental studies have shown that this variant affects talin binding. However, the clinical significance of this observation is unclear (PMID: 19608030). 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.
Illumina Clinical Services Laboratory,Illumina RCV000172517 SCV001262960 uncertain significance Primary dilated cardiomyopathy 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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