VCV002013252.5 - ClinVar

NM_023110.3(FGFR1):c.2107G>A (p.Gly703Ser)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_023110.3(FGFR1):c.2107G>A (p.Gly703Ser)

Variation ID: 2013252 Accession: VCV002013252.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.23 8: 38414231 (GRCh38) [ NCBI UCSC ] 8: 38271749 (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	Feb 8, 2023	Oct 8, 2024	Nov 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_023110.3:c.2107G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_075598.2:p.Gly703Ser	missense
NM_000604.2:c.2107G>A	NP_000595.1:p.Gly703Ser	missense
NM_001174063.2:c.2101G>A	NP_001167534.1:p.Gly701Ser	missense
NM_001174064.2:c.2077G>A	NP_001167535.1:p.Gly693Ser	missense
NM_001174065.2:c.2101G>A	NP_001167536.1:p.Gly701Ser	missense
NM_001174066.2:c.1840G>A	NP_001167537.1:p.Gly614Ser	missense
NM_001174067.2:c.2200G>A	NP_001167538.1:p.Gly734Ser	missense
NM_001354367.2:c.2101G>A	NP_001341296.1:p.Gly701Ser	missense
NM_001354368.2:c.1828G>A	NP_001341297.1:p.Gly610Ser	missense
NM_001354369.2:c.2095G>A	NP_001341298.1:p.Gly699Ser	missense
NM_001354370.2:c.1834G>A	NP_001341299.1:p.Gly612Ser	missense
NM_001410922.1:c.2095G>A	NP_001397851.1:p.Gly699Ser	missense
NM_015850.4:c.2101G>A	NP_056934.2:p.Gly701Ser	missense
NM_023105.3:c.1840G>A	NP_075593.1:p.Gly614Ser	missense
NM_023106.3:c.1834G>A	NP_075594.1:p.Gly612Ser	missense
NC_000008.11:g.38414231C>T
NC_000008.10:g.38271749C>T
NG_007729.1:g.59604G>A
LRG_993:g.59604G>A
LRG_993t1:c.2107G>A	LRG_993p1:p.Gly703Ser

... more HGVS ... less HGVS

Protein change

G610S, G612S, G701S, G614S, G693S, G699S, G703S, G734S

Other names

Canonical SPDI

NC_000008.11:38414230:C:T

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	995	1125

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 Pfeiffer syndrome	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2023	RCV002834533.3
Hypogonadotropic hypogonadism 2 with or without anosmia	Likely pathogenic (1)	criteria provided, single submitter	May 4, 2023	RCV003234594.1
FGFR1-related disorder	Uncertain significance (1)	no assertion criteria provided	Jan 19, 2024	RCV004545401.2

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.
Likely pathogenic (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypogonadotropic hypogonadism 2 with or without anosmia Affected status: yes Allele origin: inherited	Reproductive Endocrine Unit, Massachusetts General Hospital Accession: SCV003932586.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Number of individuals with the variant: 1
Uncertain significance (Nov 15, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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: SCV003215188.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 16764984‚ 23643382 Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 703 of the FGFR1 protein (p.Gly703Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 703 of the FGFR1 protein (p.Gly703Ser). This variant is present in population databases (rs768957161, gnomAD 0.007%). This missense change has been observed in individual(s) with Kallmann syndrome (PMID: 16764984). ClinVar contains an entry for this variant (Variation ID: 2013252). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. This variant disrupts the p.Gly703 amino acid residue in FGFR1. Other variant(s) that disrupt this residue have been observed in individuals with FGFR1-related conditions (PMID: 16764984, 23643382), which suggests that this may be a clinically significant amino acid residue. 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)
Uncertain significance (Jan 19, 2024)	no assertion criteria provided Method: clinical testing	FGFR1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004763378.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The FGFR1 c.2107G>A variant is predicted to result in the amino acid substitution p.Gly703Ser. This variant has been reported in an individual with Kallmann syndrome … (more) The FGFR1 c.2107G>A variant is predicted to result in the amino acid substitution p.Gly703Ser. This variant has been reported in an individual with Kallmann syndrome (Table 1, Pitteloud et al. 2006. PubMed ID: 16764984). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Gly703Arg) has also been reported in individual with Kallmann syndrome (Table 1, Pitteloud et al. 2006. PubMed ID: 16764984). Although we suspect this variant may be pathogenic, at this time, the clinical significance of the variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 703 of the FGFR1 protein (p.Gly703Ser). This variant is present in population databases (rs768957161, gnomAD 0.007%). This missense change has been observed in individual(s) with Kallmann syndrome (PMID: 16764984). ClinVar contains an entry for this variant (Variation ID: 2013252). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. This variant disrupts the p.Gly703 amino acid residue in FGFR1. Other variant(s) that disrupt this residue have been observed in individuals with FGFR1-related conditions (PMID: 16764984, 23643382), which suggests that this may be a clinically significant amino acid residue. 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.

Comment:

The FGFR1 c.2107G>A variant is predicted to result in the amino acid substitution p.Gly703Ser. This variant has been reported in an individual with Kallmann syndrome (Table 1, Pitteloud et al. 2006. PubMed ID: 16764984). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide change affecting the same amino acid (p.Gly703Arg) has also been reported in individual with Kallmann syndrome (Table 1, Pitteloud et al. 2006. PubMed ID: 16764984). Although we suspect this variant may be pathogenic, at this time, the clinical significance of the variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.	Miraoui H	American journal of human genetics	2013	PMID: 23643382
Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes.	Pitteloud N	Molecular and cellular endocrinology	2006	PMID: 16764984

Text-mined citations for this variant ...

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_023110.3(FGFR1):c.2107G>A (p.Gly703Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...