rs145387010

chr10-90918950-G-Achr10-90918950-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014391.3(ANKRD1):c.368C>T(p.Thr123Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,604,648 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T123K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: ANKRD1 NM_014391.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:7
• Conservation: PhyloP100: -0.335

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1283012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD1	NM_014391.3	c.368C>T	p.Thr123Met	missense_variant	4/9	ENST00000371697.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD1	ENST00000371697.4	c.368C>T	p.Thr123Met	missense_variant	4/9	1	NM_014391.3	P1

Frequencies

GnomAD3 genomes AF: 0.000292 AC: 43 AN: 147096 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000444

Gnomad OTH AF: 0.000489

GnomAD3 exomes AF: 0.000294 AC: 73 AN: 248014 Hom.: 1 AF XY: 0.000246 AC XY: 33 AN XY: 134294

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000531

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000321 AC: 468 AN: 1457454 Hom.: 2 Cov.: 31 AF XY: 0.000306 AC XY: 222 AN XY: 725208

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000386

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000292 AC: 43 AN: 147194 Hom.: 0 Cov.: 30 AF XY: 0.000293 AC XY: 21 AN XY: 71690

Gnomad4 AFR AF: 0.000286

Gnomad4 AMR AF: 0.0000675

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000444

Gnomad4 OTH AF: 0.000485

Alfa AF: 0.000351 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	This variant is associated with the following publications: (PMID: 31737537, 30659708, 28672880, 27143260, 28518168, 23861362, 19608031, 23572067, 23299917) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2015	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, http://exac.broadinstitute.org; 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: ANKRD1 c.368C>T (p.Thr123Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 248014 control chromosomes, predominantly at a frequency of 0.00053 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANKRD1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.368C>T has been reported in the literature in at least one individual affected with Cardiomyopathy (e.g., Arimura_2009), however without strong evidence for causality. This report therefore does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least two publications report experimental evidence evaluating an impact on protein function, suggesting that the variant may represent a gain-of-contractile-function mutation as it led to increased binding to I-band components and mislocalization to the nucleus, although the variant did incorporate correctly into the sarcomere (Arimura_2009, Crocini_2013). These findings do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 19608031, 23572067, 28518168). Ten ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments (VUS, n = 9, likely benign, n = 1) citing overlapping evidence used in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

ANKRD1-related dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 123 of the ANKRD1 protein (p.Thr123Met). This variant is present in population databases (rs145387010, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19608031, 31737537). ClinVar contains an entry for this variant (Variation ID: 191577). 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 with a negative predictive value of 80%. 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

Aug 12, 2017

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. -

Dilated cardiomyopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Dec 23, 2019

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Apr 05, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The p.T123M variant (also known as c.368C>T), located in coding exon 4 of the ANKRD1 gene, results from a C to T substitution at nucleotide position 368. The threonine at codon 123 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in one subject with hypertrophic cardiomyopathy (HCM) and may have an impact on protein function (Arimura T et al. J. Am. Coll. Cardiol., 2009 Jul;54:334-42; Crocini C et al. Basic Res. Cardiol., 2013 May;108:349). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28; Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46).This amino acid position is poorly conserved in available vertebrate species, and methionine 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. -

ANKRD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	4.5
Dann	Benign	0.79
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.074	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.35
Sift	Benign	0.19	T
Sift4G	Benign	0.13	T
Polyphen		0.0030	B
Vest4		0.74
MVP		0.37
MPC		0.17
ClinPred		0.0042	T
GERP RS		-2.3
Varity_R		0.015
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs145387010; hg19: chr10-92678707; COSMIC: COSV100792297; COSMIC: COSV100792297;