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

gnomAD frequency: 0.00001  dbSNP: rs371005117

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044961	SCV001208787	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 2	2021-08-13	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 missense change has been observed in individual(s) with clinical features of ACVRL1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 842531). 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 expected to disrupt ACVRL1 protein function. 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
PreventionGenetics, part of Exact Sciences	RCV004553579	SCV004108582	uncertain significance	ACVRL1-related disorder	2022-08-18	criteria provided, single submitter	clinical testing	The ACVRL1 c.1064A>C variant is predicted to result in the amino acid substitution p.His355Pro. This variant was reported in an individual with congenital heart disease and pulmonary arterial hypertension (Table S3, Zhu et al. 2019. PubMed ID: 31727138). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-52309835-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.