2-157774114-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001111067.4(ACVR1):c.617G>A(p.Arg206His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

ACVR1
NM_001111067.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.88

Variant links:

Genes affected

ACVR1 (HGNC:171): (activin A receptor type 1) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]

ACVR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain GS (size 29) in uniprot entity ACVR1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001111067.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 2-157774114-C-T is Pathogenic according to our data. Variant chr2-157774114-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-157774114-C-T is described in Lovd as [Pathogenic]. Variant chr2-157774114-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR1	NM_001111067.4 link	c.617G>A	p.Arg206His	missense_variant	Exon 6 of 11	ENST00000434821.7	NP_001104537.1	Q04771D3DPA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR1	ENST00000434821.7 link	c.617G>A	p.Arg206His	missense_variant	Exon 6 of 11	1	NM_001111067.4	ENSP00000405004.1		Q04771

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive myositis ossificans

Pathogenic:12

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP2 supporting, PP3 supporting -

Jan 24, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22443290). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 22443290). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279798 /PMID: 9837822 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2021

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product _moderado: PMID: 22977237; 22508565; 22351757; 21525719 - PS3_moderate.The c.617G>A;p.(Arg206His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 18309; PMID: 21525719; PMID: 19085907; PMID: 18830232; PMID: 17351709; PMID: 17077940) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (TGF_beta_GS) - PM1. This variant is not present in population databases (rs121912678- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 18830232) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Apr 06, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:4

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 206 of the ACVR1 protein (p.Arg206His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with fibrodysplasia ossificans progressiva (FOP) (PMID: 16642017, 23653868, 29482508). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 18309). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ACVR1 function (PMID: 18684712, 22508565). For these reasons, this variant has been classified as Pathogenic. -

Jun 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect with R206H acting as an activating variant that stimulates BMP signaling without requiring BMP to initiate the signaling cascade (Shen et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23918320, 20577760, 34139597, 20463014, 19929436, 22508565, 24852373, 22977237, 18684712, 25446088, 23653868, 17572636, 21525719, 22174087, 25346098, 23320317, 26055602, 25899773, 26333933, 16642017, 18979151, 27530160, 27713089, 27565519, 19543505, 26769004, 28476747, 26966495, 26626181, 30968644, 29620724, 19300893, 29482508, 29033382, 19099712, 31344178, 31240838, 32369273, 32727600, 32332674, 31785789, 19855136, 19085907, 32273545) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACVR1: PS2, PS4, PM2, PP4:Moderate, PS3:Moderate, PP3 -

Inborn genetic diseases

Pathogenic:1

Dec 14, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACVR1-related disorder

Pathogenic:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACVR1 c.617G>A variant is predicted to result in the amino acid substitution p.Arg206His. This variant has been reported to be a recurrent and de novo causative variant for fibrodysplasia ossificans progressiva (FOP) (Shore et al. 2006. PubMed ID: 16642017; Lee et al. 2009. PubMed ID: 19543505). This variant has not been reported in a large population database , indicating this variant is rare. This variant is interpreted as pathogenic. -

Epicanthus

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.R206H in ACVR1 (NM_001111067.4) is a recuurent mutation in multiple affected patients (Kaplan et al, 2009; Bocciardi R et al, 2009). Animal models have shown a similar presentation (Chakkalakal SA et al). The variant has been submitted to ClinVar as Pathogenic. The p.R206H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R206H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 206 of ACVR1 is conserved in all mammalian species. The nucleotide c.617 in ACVR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;.;D;.

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;M;M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.94

MutPred

0.88

Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);Loss of MoRF binding (P = 0.0485);

MVP

0.98

MPC

1.9

ClinPred

1.0

GERP RS

5.6

Varity_R

0.98

gMVP

0.79

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

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

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