NM_000020.3(ACVRL1):c.1246+9C>T AND not specified

Clinical significance:Benign (Last evaluated: Jul 9, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000249414.4

Allele description [Variation Report for NM_000020.3(ACVRL1):c.1246+9C>T]

NM_000020.3(ACVRL1):c.1246+9C>T

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.1246+9C>T
HGVS:
  • NC_000012.12:g.51916242C>T
  • NG_009549.1:g.13825C>T
  • NM_000020.2:c.1246+9C>T
  • NM_000020.3:c.1246+9C>TMANE SELECT
  • NM_001077401.2:c.1246+9C>T
  • LRG_543t1:c.1246+9C>T
  • LRG_543:g.13825C>T
  • NC_000012.11:g.52310026C>T
Links:
dbSNP: rs115378744
NCBI 1000 Genomes Browser:
rs115378744
Molecular consequence:
  • NM_000020.2:c.1246+9C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000020.3:c.1246+9C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001077401.2:c.1246+9C>T - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000301533PreventionGenetics,PreventionGeneticscriteria provided, single submitter
Benigngermlineclinical testing

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

SCV000711278Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Benign
(Feb 21, 2013)
germlineclinical testing

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

SCV000714198GeneDxcriteria provided, single submitter
Benign
(Feb 8, 2017)
germlineclinical testing

Citation Link,

SCV001774675Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Jul 9, 2021)
germlineclinical testing

Citation Link,

SCV001921854Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedBenigngermlineclinical testing

SCV001929726Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedBenigngermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From PreventionGenetics,PreventionGenetics, SCV000301533.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000711278.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

1246+9C>T in intron 8 of ACVRL1: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 2.7% (121/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS; dbSNP rs115378744).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From GeneDx, SCV000714198.1

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001774675.1

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

Description

Variant summary: ACVRL1 c.1246+9C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0023 in 247898 control chromosomes in the gnomAD database, including 13 homozygotes. The observed variant frequency is approximately 68.98 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACVRL1 causing Hereditary Hemorrhagic Telangiectasia phenotype (3.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1246+9C>T in individuals affected with Hereditary Hemorrhagic Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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

From Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus, SCV001921854.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001929726.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 24, 2021

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