VCV001712486.5 - ClinVar

NM_023110.3(FGFR1):c.1922A>G (p.Asp641Gly)

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.

(3)

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_023110.3(FGFR1):c.1922A>G (p.Asp641Gly)

Variation ID: 1712486 Accession: VCV001712486.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.23 8: 38414834 (GRCh38) [ NCBI UCSC ] 8: 38272352 (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 30, 2022	Feb 28, 2024	Sep 20, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_023110.3:c.1922A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075598.2:p.Asp641Gly	missense
NM_000604.2:c.1922A>G	NP_000595.1:p.Asp641Gly	missense
NM_001174063.2:c.1916A>G	NP_001167534.1:p.Asp639Gly	missense
NM_001174064.2:c.1892A>G	NP_001167535.1:p.Asp631Gly	missense
NM_001174065.2:c.1916A>G	NP_001167536.1:p.Asp639Gly	missense
NM_001174066.2:c.1655A>G	NP_001167537.1:p.Asp552Gly	missense
NM_001174067.2:c.2015A>G	NP_001167538.1:p.Asp672Gly	missense
NM_001354367.2:c.1916A>G	NP_001341296.1:p.Asp639Gly	missense
NM_001354368.2:c.1643A>G	NP_001341297.1:p.Asp548Gly	missense
NM_001354369.2:c.1910A>G	NP_001341298.1:p.Asp637Gly	missense
NM_001354370.2:c.1649A>G	NP_001341299.1:p.Asp550Gly	missense
NM_001410922.1:c.1910A>G	NP_001397851.1:p.Asp637Gly	missense
NM_015850.4:c.1916A>G	NP_056934.2:p.Asp639Gly	missense
NM_023105.3:c.1655A>G	NP_075593.1:p.Asp552Gly	missense
NM_023106.3:c.1649A>G	NP_075594.1:p.Asp550Gly	missense
NC_000008.11:g.38414834T>C
NC_000008.10:g.38272352T>C
NG_007729.1:g.59001A>G
LRG_993:g.59001A>G
LRG_993t1:c.1922A>G	LRG_993p1:p.Asp641Gly

... more HGVS ... less HGVS

Protein change

D548G, D550G, D552G, D631G, D637G, D639G, D641G, D672G

Other names

Canonical SPDI

NC_000008.11:38414833:T:C

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

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.
FGFR1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	998	-

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.
Hartsfield-Bixler-Demyer syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 20, 2022	RCV002294741.2
Hypogonadotropic hypogonadism 2 with or without anosmia Pfeiffer syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	May 30, 2024	RCV003101705.4

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hartsfield-Bixler-Demyer syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Wangler Lab, Baylor College of Medicine Accession: SCV002587795.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022	Publications: PubMed (2) PubMed: 23812909‚ 26931467 Comment: This missense FGFR1 variant at c.1922A>G (p.D641G) was seen on exome through the Texome project (R01HG011795) as a de novo variant in the patient (PS2). … (more) This missense FGFR1 variant at c.1922A>G (p.D641G) was seen on exome through the Texome project (R01HG011795) as a de novo variant in the patient (PS2). This variant is found in the tyrosine kinase domain of FGFR1, where heterozygous variants associated with Hartsfield syndrome cluster (PMID: 23812909, 26931467) (PM1).An allelic variant (p.D641N) has been previously identified de novo in an individual with FGFR1-related Hartsfield syndrome (PS1). This variant was found to be functionally defective and consistent with the dominant negative mechanism proposed for variants associated with Hartsfield syndrome (PMID: 26931467) (PS3). It has not been observed in gnomAD (PM2).This missense variant is predicted to be deleterious (CADD: 31.000) (PP3), and there is high conservation of this residue. We classify this variant as pathogenic. (less) Age: 0-9 years Sex: male
Pathogenic (Sep 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hartsfield-Bixler-Demyer syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835626.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Uncertain significance (May 14, 2022)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: Claim with insufficient supporting evidence Source: ClinGen	Pfeiffer syndrome Hypogonadotropic hypogonadism 2 with or without anosmia Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003199337.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Comment: This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 641 of the FGFR1 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 641 of the FGFR1 protein (p.Asp641Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR1 protein function. 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. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This missense FGFR1 variant at c.1922A>G (p.D641G) was seen on exome through the Texome project (R01HG011795) as a de novo variant in the patient (PS2). This variant is found in the tyrosine kinase domain of FGFR1, where heterozygous variants associated with Hartsfield syndrome cluster (PMID: 23812909, 26931467) (PM1).An allelic variant (p.D641N) has been previously identified de novo in an individual with FGFR1-related Hartsfield syndrome (PS1). This variant was found to be functionally defective and consistent with the dominant negative mechanism proposed for variants associated with Hartsfield syndrome (PMID: 26931467) (PS3). It has not been observed in gnomAD (PM2).This missense variant is predicted to be deleterious (CADD: 31.000) (PP3), and there is high conservation of this residue. We classify this variant as pathogenic.

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 641 of the FGFR1 protein (p.Asp641Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR1 protein function. 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.

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
Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome.	Hong S	Human molecular genetics	2016	PMID: 26931467
FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.	Simonis N	Journal of medical genetics	2013	PMID: 23812909

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_023110.3(FGFR1):c.1922A>G (p.Asp641Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...