NM_000020.3(ACVRL1):c.917C>T (p.Ala306Val) AND Telangiectasia, hereditary hemorrhagic, type 2

Clinical significance:Uncertain significance (Last evaluated: Aug 8, 2020)

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:
RCV001000664.3

Allele description [Variation Report for NM_000020.3(ACVRL1):c.917C>T (p.Ala306Val)]

NM_000020.3(ACVRL1):c.917C>T (p.Ala306Val)

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.917C>T (p.Ala306Val)
HGVS:
  • NC_000012.12:g.51915369C>T
  • NG_009549.1:g.12952C>T
  • NM_000020.3:c.917C>TMANE SELECT
  • NM_001077401.2:c.917C>T
  • NP_000011.2:p.Ala306Val
  • NP_001070869.1:p.Ala306Val
  • LRG_543t1:c.917C>T
  • LRG_543:g.12952C>T
  • NC_000012.11:g.52309153C>T
  • NM_000020.2:c.917C>T
Protein change:
A306V
Links:
dbSNP: rs150038846
NCBI 1000 Genomes Browser:
rs150038846
Molecular consequence:
  • NM_000020.3:c.917C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.917C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Telangiectasia, hereditary hemorrhagic, type 2 (HHT2)
Synonyms:
Telangiectasia, hereditary hemorrhagic, type II; Osler Weber Rendu syndrome type 2
Identifiers:
MONDO: MONDO:0010880; MedGen: C1838163; Orphanet: 774; OMIM: 600376

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001157692ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Mar 24, 2019)
germlineclinical testing

Citation Link,

SCV001270872Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 27, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001485952Invitaecriteria provided, single submitter
Uncertain significance
(Aug 8, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

National mutation study among Danish patients with hereditary haemorrhagic telangiectasia.

Tørring PM, Brusgaard K, Ousager LB, Andersen PE, Kjeldsen AD.

Clin Genet. 2014 Aug;86(2):123-33. doi: 10.1111/cge.12269. Epub 2013 Oct 3.

PubMed [citation]
PMID:
24001356

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186
See all PubMed Citations (3)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001157692.1

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

Description

The ACVRL1 c.917C>T; p.Ala306Val variant (rs150038846), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is found in the general population with an overall allele frequency of 0.01% (25/282490 alleles) in the Genome Aggregation Database. Other amino acid substitutions at this codon (p.Ala306Glu, p.Ala306Pro) have been reported in individuals with hereditary haemorrhagic telangiectasia (HHT) (Lesca 2004, Torring 2014), and p.Ala306Pro exhibits altered localization and defective activity (Alaa El Din 2015), although it is uncertain if both other variants at this position are disease-causing. The alanine at codon 306 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that the p.Ala306Val variant is tolerated. Although the allele frequency of ACVRL1 p.Ala306Val is high for the known prevalence of HHT, due to limited clinical information and the reports of other amino acid substitutions at the same residue, the clinical significance of this variant is uncertain at this time. References: Alaa El Din F et al. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS One. 2015 Jul 15;10(7):e0132111. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Torring PM et al. National mutation study among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2014 Aug;86(2):123-33.

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

From Illumina Clinical Services Laboratory,Illumina, SCV001270872.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

From Invitae, SCV001485952.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces alanine with valine at codon 306 of the ACVRL1 protein (p.Ala306Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs150038846, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ACVRL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 811065). 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 tolerated, 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.

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

Last Updated: Oct 7, 2021

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