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NM_000020.3(ACVRL1):c.1313T>C (p.Met438Thr) AND Telangiectasia, hereditary hemorrhagic, type 2

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Feb 9, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000640434.16

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1313T>C (p.Met438Thr)]

NM_000020.3(ACVRL1):c.1313T>C (p.Met438Thr)

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.1313T>C (p.Met438Thr)
HGVS:
  • NC_000012.12:g.51919051T>C
  • NG_009549.1:g.16634T>C
  • NM_000020.3:c.1313T>CMANE SELECT
  • NM_001077401.2:c.1313T>C
  • NP_000011.2:p.Met438Thr
  • NP_000011.2:p.Met438Thr
  • NP_001070869.1:p.Met438Thr
  • LRG_543t1:c.1313T>C
  • LRG_543:g.16634T>C
  • LRG_543p1:p.Met438Thr
  • NC_000012.11:g.52312835T>C
  • NM_000020.2:c.1313T>C
Protein change:
M438T
Links:
dbSNP: rs1555153828
NCBI 1000 Genomes Browser:
rs1555153828
Molecular consequence:
  • NM_000020.3:c.1313T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001077401.2:c.1313T>C - 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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000762025Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Feb 9, 2021) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001156569ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Likely pathogenic
(Nov 7, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis.

McDonald J, Damjanovich K, Millson A, Wooderchak W, Chibuk JM, Stevenson DA, Gedge F, Bayrak-Toydemir P.

Clin Genet. 2011 Apr;79(4):335-44. doi: 10.1111/j.1399-0004.2010.01596.x. Epub 2010 Dec 16.

PubMed [citation]
PMID:
21158752

Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management.

Mattassi R, Manara E, Colombo PG, Manara S, Porcella A, Bruno G, Bruson A, Bertelli M.

J Vasc Surg. 2018 Mar;67(3):922-932.e11. doi: 10.1016/j.jvs.2017.02.034. Epub 2017 Jun 24.

PubMed [citation]
PMID:
28655553
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000762025.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met438 amino acid residue in ACVRL1. Other variant(s) that disrupt this residue have been observed in individuals with ACVRL1-related conditions (PMID: 21158752, 28655553), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393, 31327192, Invitae). ClinVar contains an entry for this variant (Variation ID: 533343). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 438 of the ACVRL1 protein (p.Met438Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156569.1

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

Description

The ACVRL1 c.1313T>C; p.Met438Thr variant is reported in the literature in at least one individual affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer 2005). This variant is reported in ClinVar (Variation ID: 533343), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 438 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.1313T>G, p.Met438Arg; c.1313T>A, p.Met438Lys) have been reported in individuals with vascular anomalies (Mattassi 2018, McDonald 2011). Based on available information, the p.Met438Thr variant is considered to be likely pathogenic. References: Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Mattassi R et al. Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management. J Vasc Surg. 2018 Mar;67(3):922-932.e11. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44.

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

Last Updated: Nov 3, 2024