2-157774114-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. R206R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACVR1 NM_001111067.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain GS (size 29) in uniprot entity ACVR1_HUMAN there are 7 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/exons	MANE	UniProt
ACVR1	NM_001111067.4	c.617G>A	p.Arg206His	missense_variant	6/11	ENST00000434821.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR1	ENST00000434821.7	c.617G>A	p.Arg206His	missense_variant	6/11	1	NM_001111067.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myositis ossificans Pathogenic:12

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 06, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 17, 2020	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 25, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Feb 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018309, PMID:16642017). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30379592). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.948>=0.6, 3CNET: 0.924>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 24, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ACVR1: PP4:Strong, PS2, PS4, PM2, PS3:Moderate, PP3 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2017

- -

ACVR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

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	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	33
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	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.89	D
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	D
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

Other links and lift over

dbSNP: rs121912678; hg19: chr2-158630626; COSMIC: COSV55115924; COSMIC: COSV55115924;