ClinVar Miner

Submissions for variant NM_000020.3(ACVRL1):c.1064A>C (p.His355Pro)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001044961 SCV001208787 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2019-06-05 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 355 of the ACVRL1 protein (p.His355Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs371005117, ExAC 0.002%). This variant has not been reported in the literature in individuals with ACVRL1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001044961 SCV001473326 uncertain significance Telangiectasia, hereditary hemorrhagic, type 2 2019-09-13 criteria provided, single submitter clinical testing The ACVRL1 c.1064A>C; p.His355Pro variant (rs371005117), has been previously identified in one individual included in a cohort of pulmonary arterial hypertension patients (Zhu 2019; preprint upload). It is also located in a highly conserved region of ACVRL1 (Alamut v.2.11) and nearby missense variants (p.Ala352Asp, p.Ala352Pro, p.Met354Lys) have been observed in hereditary haemorrhagic telangiectasia (HHT) patients (Olivieri 2002, Prigoda 2006, Wehner 2006). The p.His355Pro variant is found in the general population with an allele frequency in non-Finnish Europeans of 0.003% (3/113,224 alleles) in the Genome Aggregation Database. Computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious to protein function. However, based on the available information, the clinical significance of this variant is uncertain. References: Olivieri C et al. Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. J Med Genet. 2002 Jul;39(7):E39. Prigoda NL et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet. 2006 Sep;43(9):722-8. Epub 2006 May 11. Wehner LE et al. Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clin Genet. 2006 Mar;69(3):239-45. Zhu N et al. Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension. 2013. bioRxiv doi: 10.1101/550327v1

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.