ClinVar Miner

Submissions for variant NM_014391.3(ANKRD1):c.368C>T (p.Thr123Met) (rs145387010)

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Total submissions: 10
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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 RCV000171828 SCV000050855 uncertain significance Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724536 SCV000230347 uncertain significance not provided 2015-02-09 criteria provided, single submitter clinical testing
GeneDx RCV000183297 SCV000235724 uncertain significance not specified 2016-04-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANKRD1 gene. Functional studies revealed that T123M correctly incorporates into the sarcomere in standard conditions but may lead to slightly higher force and velocities of contraction and relaxation compared to wild-type (Crocini et al., 2013). However, this data is not sufficient to support pathogenicity. The T123M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however it was reported in the 1000 Genomes project in approximately 0.2% of alleles in individuals of African descent. Although T123M results in 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, this variant is not conserved across species. Consequently, in silico analysis predicts T123M predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000183297 SCV000271502 uncertain significance not specified 2015-04-18 criteria provided, single submitter clinical testing The p.Thr123Met variant in ANKRD1 has been reported in 1 individual with HCM (Ar imura 2009). In vitro functional studies provide some evidence that this variant may impact protein function (Arimura 2009, Crocini 2013). However, these types of sometimes do not accurately represent biological function. The p.Thr123Met va riant has also been identified in 20/66418 European chromosomes by the Exome Agg regation Consortium (ExAC,; dbSNP rs145387010). T hreonine (Thr) at position 123 is not conserved in evolution and 2 mammals (oran gutan and cow) carry a methionine (Met) at this position, raising the possibilit y that this change may be tolerated. In summary, the available data is conflicti ng and the clinical significance of the p.Thr123Met variant is uncertain.
Invitae RCV000458316 SCV000553446 uncertain significance ANKRD1-related dilated cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 123 of the ANKRD1 protein (p.Thr123Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs145387010, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 19608031). ClinVar contains an entry for this variant (Variation ID: 191577). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000619346 SCV000736082 uncertain significance Cardiovascular phenotype 2018-11-30 criteria provided, single submitter clinical testing Insufficient evidence
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000183297 SCV001159963 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing The ANKRD1 c.368C>T; p.Thr123Met variant (rs145387010) is reported in the literature in at least one individual affected with hypertrophic cardiomyopathy (Arimura 2009). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 191577), and is found in the non-Finnish European population with an allele frequency of 0.053% (68/128218 alleles, including a single homozygote) in the Genome Aggregation Database. Functional analyses demonstrate slightly altered protein interactions and functional effects (Arimura 2009, Crocini 2013). The threonine at codon 123 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr123Met variant is uncertain at this time. References: Arimura T et al. Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009 Jul 21;54(4):334-42. Crocini et al. Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue. Basic Res Cardiol. 2013 May;108(3):349.
Illumina Clinical Services Laboratory,Illumina RCV001104802 SCV001261695 uncertain significance Primary dilated cardiomyopathy 2017-08-12 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256727 SCV001433133 uncertain significance Dilated cardiomyopathy 1A 2019-12-23 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000724536 SCV000924751 uncertain significance not provided 2016-06-20 no assertion criteria provided provider interpretation

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