VCV003255136.1 - ClinVar

NM_023110.3(FGFR1):c.2423C>G (p.Pro808Arg)

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.

(1)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_023110.3(FGFR1):c.2423C>G (p.Pro808Arg)

Variation ID: 3255136 Accession: VCV003255136.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.23 8: 38413674 (GRCh38) [ NCBI UCSC ] 8: 38271192 (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	Jul 23, 2024	Jul 23, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_023110.3:c.2423C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075598.2:p.Pro808Arg	missense
NM_001174063.2:c.2417C>G	NP_001167534.1:p.Pro806Arg	missense
NM_001174064.2:c.2393C>G	NP_001167535.1:p.Pro798Arg	missense
NM_001174065.2:c.2417C>G	NP_001167536.1:p.Pro806Arg	missense
NM_001174066.2:c.2156C>G	NP_001167537.1:p.Pro719Arg	missense
NM_001174067.2:c.2516C>G	NP_001167538.1:p.Pro839Arg	missense
NM_001354367.2:c.2286+244C>G		intron variant
NM_001354368.2:c.2144C>G	NP_001341297.1:p.Pro715Arg	missense
NM_001354369.2:c.2280+244C>G		intron variant
NM_001354370.2:c.2019+244C>G		intron variant
NM_001410922.1:c.2411C>G	NP_001397851.1:p.Pro804Arg	missense
NM_015850.4:c.2417C>G	NP_056934.2:p.Pro806Arg	missense
NM_023105.3:c.2156C>G	NP_075593.1:p.Pro719Arg	missense
NM_023106.3:c.2150C>G	NP_075594.1:p.Pro717Arg	missense
NC_000008.11:g.38413674G>C
NC_000008.10:g.38271192G>C
NG_007729.1:g.60161C>G
NG_113979.1:g.689G>C
LRG_993:g.60161C>G
LRG_993t1:c.2423C>G	LRG_993p1:p.Pro808Arg

... more HGVS ... less HGVS

Protein change

P715R, P717R, P719R, P798R, P804R, P806R, P808R, P839R

Other names

Canonical SPDI

NC_000008.11:38413673:G: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	989	1119

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.
Hypogonadotropic hypogonadism 2 with or without anosmia	Uncertain significance (1)	criteria provided, single submitter	Jul 17, 2023	RCV004595319.1

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.
Uncertain significance (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypogonadotropic hypogonadism 2 with or without anosmia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086490.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 18034870‚ 23812909‚ 26942290 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 (HH2; MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR1-related disease. Loss of function missense variants and variants predicted to undergo nonsense-mediated decay have been reported to cause Hartsfield syndrome (MIM#615465) and hypogonadotropic hypogonadism-2 (HH2; MIM#147950). Gain of function missense variants have been reported to cause encephalocraniocutaneous lipomatosis, somatic mosaic (MIM#613001) and osteoglophonic dysplasia (MIM#166250). Additional missense variants have been reported in patients with Jackson-Weiss syndrome (MIM#123150), Pfeiffer syndrome (MIM#101600) or trigonocephaly 1 (MIM#190440) however, the mechanism of these variants is unknown (OMIM, PMID: 18034870, 23812909, 26942290). (I) 0107 - This gene is associated with autosomal dominant disease. Biallelic missense variants have been rarely reported in patients with Hartsfield syndrome (PMID: 23812909). (I) 0115 - Variants in this gene are known to have variable expressivity in patients with HH2 (PMID: 18034870). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.	Bennett JT	American journal of human genetics	2016	PMID: 26942290
FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.	Simonis N	Journal of medical genetics	2013	PMID: 23812909
Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome.	Kim SH	Journal of neuroendocrinology	2008	PMID: 18034870

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_023110.3(FGFR1):c.2423C>G (p.Pro808Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...