VCV000692054.10 - ClinVar

NM_001451.3(FOXF1):c.691_698del (p.Ala231fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001451.3(FOXF1):c.691_698del (p.Ala231fs)

Variation ID: 692054 Accession: VCV000692054.10

Type and length

Microsatellite, 8 bp

Location

Cytogenetic: 16q24.1 16: 86511252-86511259 (GRCh38) [ NCBI UCSC ] 16: 86544858-86544865 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 20, 2019	Oct 26, 2024	Oct 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001451.3:c.691_698del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001442.2:p.Ala231fs	frameshift
NM_001451.3:c.691_698delGCGGCGGC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001451.2:c.691_698del
NC_000016.10:g.86511252GCGGCGGC[1]
NC_000016.9:g.86544858GCGGCGGC[1]
NG_016273.1:g.5726GCGGCGGC[1]

... more HGVS ... less HGVS

Protein change

A231fs

Other names

Canonical SPDI

NC_000016.10:86511251:GCGGCGGCGCGGCGGC:GCGGCGGC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1597291554 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FOXF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Alveolar capillary dysplasia with pulmonary venous misalignment	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 23, 2024	RCV000853342.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 16, 2023	RCV001269782.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 04, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ALVEOLAR CAPILLARY DYSPLASIA WITH MISALIGNMENT OF PULMONARY VEINS Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996204.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: This frameshifting variant in exon 1 of 2 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. … (more) This frameshifting variant in exon 1 of 2 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in a patient with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) (PMID: 23505205). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.691_698delGCGGCGGC (p.Ala231ArgfsTer61) variant is classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Jul 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alveolar capillary dysplasia with pulmonary venous misalignment Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001430614.1 First in ClinVar: Aug 22, 2020 Last updated: Aug 22, 2020	Publications: PubMed (1) PubMed: 23505205 Comment: This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. It has been reported to be … (more) This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. It has been reported to be de novo in a patient presenting with alveolar capillary dysplasia with misalignment of pulmonary veins. This variant is absent from a large population dataset. It has a ClinVar entry. We consider this variant to be pathogenic. (less)
Pathogenic (Oct 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450037.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1
Pathogenic (Sep 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alveolar capillary dysplasia with pulmonary venous misalignment Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023750.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004028075.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23505205, 31641027, 31436901, 32036090, 33578219, 31199666) (less)
Pathogenic (Oct 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alveolar capillary dysplasia with pulmonary venous misalignment (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV005375476.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Clinical Features: Pulmonary arterial hypertension (present) , Alveolar capillary dysplasia (present)
Pathogenic (Oct 01, 2019)	no assertion criteria provided Method: research	Alveolar capillary dysplasia with pulmonary venous misalignment Affected status: yes Allele origin: de novo	Stankiewicz Research Laboratory, Baylor College of Medicine Accession: SCV001055837.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Number of individuals with the variant: 3

Comment:

This frameshifting variant in exon 1 of 2 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in a patient with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) (PMID: 23505205). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.691_698delGCGGCGGC (p.Ala231ArgfsTer61) variant is classified as pathogenic.

Comment:

This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. It has been reported to be de novo in a patient presenting with alveolar capillary dysplasia with misalignment of pulmonary veins. This variant is absent from a large population dataset. It has a ClinVar entry. We consider this variant to be pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23505205, 31641027, 31436901, 32036090, 33578219, 31199666)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.	Sen P	Human mutation	2013	PMID: 23505205

Text-mined citations for rs1597291554 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001451.3(FOXF1):c.691_698del (p.Ala231fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1597291554 ...