Genetic Variant ANKRD1:p.Leu75ThrfsTer8 (chr10-90919253-G-GT) – ACMG Classification: Uncertain_significance (2 pts)

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 0.843

Variant links:

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]

ANKRD1 links:

Genome browser will be placed here

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 link	c.222dupA	p.Leu75ThrfsTer8	frameshift_variant	Exon 3 of 9	ENST00000371697.4	NP_055206.2	Q15327A0A384NYH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD1	ENST00000371697.4 link	c.222dupA	p.Leu75ThrfsTer8	frameshift_variant	Exon 3 of 9	1	NM_014391.3	ENSP00000360762.3		Q15327

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000969

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

242674

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

131470

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000564

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000210

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000169

AC:

246

AN:

1454084

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

131

AN XY:

723360

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000217

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.000105

AC:

AN:

151792

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74120

show subpopulations

Gnomad4 AFR

AF:

0.0000969

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000144

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Sep 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:2

Jan 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 14, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ANKRD1-related dilated cardiomyopathy

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

10-90919253-GT-GTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over