NM_000020.3(ACVRL1):c.905T>C (p.Leu302Pro) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 14, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002370004.3

Allele description [Variation Report for NM_000020.3(ACVRL1):c.905T>C (p.Leu302Pro)]

NM_000020.3(ACVRL1):c.905T>C (p.Leu302Pro)

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_000020.3(ACVRL1):c.905T>C (p.Leu302Pro)

HGVS:

NC_000012.12:g.51915357T>C
NG_009549.1:g.12940T>C
NM_000020.3:c.905T>CMANE SELECT
NM_001077401.2:c.905T>C
NP_000011.2:p.Leu302Pro
NP_000011.2:p.Leu302Pro
NP_001070869.1:p.Leu302Pro
LRG_543t1:c.905T>C
LRG_543:g.12940T>C
LRG_543p1:p.Leu302Pro
NC_000012.11:g.52309141T>C
NM_000020.2:c.905T>C

Protein change:

L302P

Links:

dbSNP: rs1565594217

NCBI 1000 Genomes Browser:

rs1565594217

Molecular consequence:

NM_000020.3:c.905T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001077401.2:c.905T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002688512	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 14, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15880681, 25557927, 32573726 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002688512

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 14, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients.

Schulte C, Geisthoff U, Lux A, Kupka S, Zenner HP, Blin N, Pfister M.

Hum Mutat. 2005 Jun;25(6):595.

PubMed [citation]

PMID:: 15880681

A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.

Kerr G, Sheldon H, Chaikuad A, Alfano I, von Delft F, Bullock AN, Harris AL.

Angiogenesis. 2015 Apr;18(2):209-17. doi: 10.1007/s10456-014-9457-y. Epub 2015 Jan 4.

PubMed [citation]

PMID:: 25557927
PMCID:: PMC4363482

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002688512.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.L302P variant (also known as c.905T>C), located in coding exon 6 of the ACVRL1 gene, results from a T to C substitution at nucleotide position 905. The leucine at codon 302 is replaced by proline, an amino acid with similar properties. This variant has been detected in multiple individuals with clinical features of hereditary hemorrhagic telangiectasia in the literature and at other laboratories (Shovlin CL et al. Blood, 2020 10;136:1907-1918). Based on internal structural analysis, L302P is moderately destabilizing to the local structure and more deleterious than nearby likely pathogenic variants (Kerr G et al. Angiogenesis, 2015 Apr;18:209-17). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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