ClinVar Miner

Submissions for variant NM_014391.3(ANKRD1):c.313C>T (p.Pro105Ser)

gnomAD frequency: 0.00037  dbSNP: 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
Eurofins Ntd Llc (ga) RCV000725419 SCV000336823 uncertain significance not provided 2015-11-04 criteria provided, single submitter clinical testing
GeneDx RCV000725419 SCV000520827 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing Reported in association with cardiomyopathy in individuals in published literature (Moulik et al., 2009); Reported in one individual 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 23299917, 19608030, 26187847, 27896284, 28672880, 30659708, 34426522, 30847666, 23861362)
Ambry Genetics RCV000622147 SCV000736424 uncertain significance Cardiovascular phenotype 2023-03-03 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 a 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 another 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000690391 SCV000818075 uncertain significance ANKRD1-related dilated cardiomyopathy 2023-09-26 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects ANKRD1 function (PMID: 19608030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD1 protein function. ClinVar contains an entry for this variant (Variation ID: 192112). This missense change has been observed in individual(s) with clinical features of ANKRD1-related conditions (PMID: 19608030, 30847666). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 105 of the ANKRD1 protein (p.Pro105Ser). This variant is present in population databases (rs148189486, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant.
Illumina Laboratory Services, 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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