rs776659587
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014391.3(ANKRD1):c.222dupA(p.Leu75ThrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,605,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
ANKRD1
NM_014391.3 frameshift
NM_014391.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.843
Genes affected
ANKRD1 (HGNC:15819): (ankyrin repeat domain 1) The protein encoded by this gene is localized to the nucleus of endothelial cells and is induced by IL-1 and TNF-alpha stimulation. Studies in rat cardiomyocytes suggest that this gene functions as a transcription factor. Interactions between this protein and the sarcomeric proteins myopalladin and titin suggest that it may also be involved in the myofibrillar stretch-sensor system. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ANKRD1 | NM_014391.3 | c.222dupA | p.Leu75ThrfsTer8 | frameshift_variant | Exon 3 of 9 | ENST00000371697.4 | NP_055206.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 151792Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000103 AC: 25AN: 242674Hom.: 0 AF XY: 0.000106 AC XY: 14AN XY: 131470
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GnomAD4 exome AF: 0.000169 AC: 246AN: 1454084Hom.: 0 Cov.: 32 AF XY: 0.000181 AC XY: 131AN XY: 723360
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GnomAD4 genome 0.000105 AC: 16AN: 151792Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4AN XY: 74120
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2024 | Reported in individuals with various types of cardiomyopathy, including hypertrophic, dilated, and noncompaction in published literature (PMID: 30847666, 29447731, 33996946, 36129056); Identified in an individual with a personal history of noncompaction cardiomyopathy and left ventricular hypertrophy and a family history of HCM; however, this individual was also found to harbor a pathogenic variant in MYBPC3 that segregated with disease in his affected father (PMID: 28794111); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 29447731, 33996946, 30847666, 36129056, 28794111) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 20, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 29, 2015 | The p.Leu75fs variant in ANKRD1 has not been previously reported in individuals with cardiomyopathy, but has been identified in 11/60640 (0.02%) European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) . This variant is predicted to cause a frameshift, which alters the protein?s am ino acid sequence beginning at position 75 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a t runcated or absent protein. Although this variant is expected severely impact th e protein, there is insufficient evidence to conclusively establish or rule out the role of ANKRD1 in disease and the spectrum of variants that can cause diseas e is poorly defined. In summary, the clinical significance of the p.Leu75fs vari ant is uncertain. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Oct 14, 2016 | - - |
ANKRD1-related dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | This sequence change creates a premature translational stop signal (p.Leu75Thrfs*8) in the ANKRD1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ANKRD1 cause disease. This variant is present in population databases (rs776659587, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 28794111, 30847666, 33996946). ClinVar contains an entry for this variant (Variation ID: 201670). 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. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 30, 2018 | This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2024 | The c.222dupA variant, located in coding exon 3 of the ANKRD1 gene, results from a duplication of A at nucleotide position 222, causing a translational frameshift with a predicted alternate stop codon (p.L75Tfs*8). This variant was reported to co-occurr with an MYBPC3 mutation in a proband with features of hypertrophic and non-compaction cardiomyopathy (van Velzen HG. Circ Cardiovasc Genet. 2017 Aug;10(4)). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of ANKRD1 has not been clearly established as a mechanism of disease. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
ANKRD1-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 13, 2024 | The ANKRD1 c.222dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu75Thrfs*8). This variant has been reported in multiple individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy, and noncompaction cardiomyopathy (van Velzen et al. 2017. PubMed ID: 28794111; Online Table 3, van Waning et al. 2018. PubMed ID: 29447731; Online Supplementary File 2, van Lint et al. 2019. PubMed ID: 30847666; Table S8, Xiao et al. 2021. PubMed ID: 33996946). However, in at least one individual, this variant co-occurred with a pathogenic nonsense variant in a cardiomyopathy-associated gene that could explain the cardiac phenotypes (van Velzen et al. 2017. PubMed ID: 28794111). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/201670/). Few chain-terminating variants in ANKRD1 are reported and loss of function has not been conclusively established as a mechanism for ANKRD1-related disorders. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at