NM_000020.2(ACVRL1):c.200G>A (p.Arg67Gln) AND not provided

Clinical significance:Pathogenic (Last evaluated: Jul 8, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000200439.2

Allele description [Variation Report for NM_000020.2(ACVRL1):c.200G>A (p.Arg67Gln)]

NM_000020.2(ACVRL1):c.200G>A (p.Arg67Gln)

Gene:
ACVRL1:activin A receptor like type 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q13.13
Genomic location:
Preferred name:
NM_000020.2(ACVRL1):c.200G>A (p.Arg67Gln)
Other names:
p.R67Q:CGG>CAG
HGVS:
  • NC_000012.12:g.51913237G>A
  • NG_009549.1:g.10820G>A
  • NM_000020.2:c.200G>A
  • NM_001077401.2:c.200G>A
  • NP_000011.2:p.Arg67Gln
  • NP_001070869.1:p.Arg67Gln
  • LRG_543t1:c.200G>A
  • LRG_543:g.10820G>A
  • LRG_543p1:p.Arg67Gln
  • NC_000012.11:g.52307021G>A
  • P37023:p.Arg67Gln
Protein change:
R67Q
Links:
UniProtKB: P37023#VAR_006206; dbSNP: rs863223414
NCBI 1000 Genomes Browser:
rs863223414
Molecular consequence:
  • NM_000020.2:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.200G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000249633GeneDxcriteria provided, single submitter
Pathogenic
(Feb 2, 2018)
germlineclinical testing

Citation Link,

SCV000883351ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jul 18, 2017)
germlineclinical testing

Citation Link,

SCV001713595Mayo Clinic Laboratories, Mayo Cliniccriteria provided, single submitter
Pathogenic
(Jul 8, 2019)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical testing

Citations

PubMed

DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population.

Lenato GM, Lastella P, Di Giacomo MC, Resta N, Suppressa P, Pasculli G, SabbĂ  C, Guanti G.

Hum Mutat. 2006 Feb;27(2):213-4.

PubMed [citation]
PMID:
16429404
See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000249633.13

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The R67Q pathogenic variant in the ACVRL1 gene has been reported in numerous individuals with HHT (Berg et. al., 1997; Schulte et al., 2005; Sadick et al., 2009; Lenato et al., 2006; Canzonieri et al., 2014). Berg et al. (1997) originally described R67Q in an individual with HHT and was absent from at least 200 control chromosomes. R67Q has been observed in at least three other individuals with HHT (Schulte et al. 2005; Sadick et al., 2009; Canzonieri et al., 2014). Family studies demonstrated R67Q co-segregated with HHT in two families and was absent from 200 control alleles (Lenato et al., 2006). R67Q results in a semi-conservative amino acid substitution of Arginine at a position that is conserved across species. Variants in this same residue (R67W) and in nearby residues (H66P, G68C, C69R, C69Y, C69F) have been reported in association with HHT, further supporting the functional importance of this region of the protein. Furthermore, the R67Q mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R67Q in the ACVRL1 gene is interpreted as a pathogenic variant. This variant was found in HHT-PANCARD panel(s).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000883351.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ACVRL1 c.200G>A; p.Arg67Gln variant (rs863223414) has been reported in multiple unrelated individuals and families with hereditary hemorrhagic telangiectasia (Berg 1997, Canzonieri 2014, Giordano 2006, Lenato 2006, Olivieri 2007, Schulte 2005). This variant is reported in the ClinVar database (Variation ID: 212803), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The arginine at codon 67 is highly conserved, and computational algorithms (SIFT, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg67Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/212803/ Berg JN et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet. 1997 Jul;61(1):60-7. Canzonieri C et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genet Med. 2014 Jan;16(1):3-10. Giordano P et al. Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician. J Thromb Haemost. 2006 Jun;4(6):1237-45. Lenato GM et al. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Hum Mutat. 2006 Feb;27(2):213-4. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001713595.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (9)

Description

PS3, PS4, PM2, PM5, PP1, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

Last Updated: Jun 14, 2021

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