8-38421836-C-T

Variant names:

• chr8-38421836-C-T
• rs886037634
• NM_023110.3:c.1042G>A

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_023110.3(FGFR1):​c.1042G>A​(p.Gly348Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G348E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.91

Genes affected

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ENSG00000255201 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_023110.3 (FGFR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 11) in uniprot entity FGFR1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_023110.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-38421835-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 8-38421836-C-T is Pathogenic according to our data. Variant chr8-38421836-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 50849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38421836-C-T is described in Lovd as [Likely_pathogenic]. Variant chr8-38421836-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1042G>A	p.Gly348Arg	missense_variant	Exon 8 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1042G>A	p.Gly348Arg	missense_variant	Exon 8 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1036G>A	p.Gly346Arg	missense_variant	Exon 8 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1036G>A	p.Gly346Arg	missense_variant	Exon 9 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1036G>A	p.Gly346Arg	missense_variant	Exon 8 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.775G>A	p.Gly259Arg	missense_variant	Exon 7 of 17	1		ENSP00000348537.5
FGFR1	ENST00000326324.10	c.769G>A	p.Gly257Arg	missense_variant	Exon 7 of 17	1		ENSP00000327229.6
FGFR1	ENST00000397103.5	c.814+1189G>A		intron_variant	Intron 6 of 15	5		ENSP00000380292.1
FGFR1	ENST00000487647.5	n.*733G>A		non_coding_transcript_exon_variant	Exon 7 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*733G>A		3_prime_UTR_variant	Exon 7 of 12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:3

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The variant has been classified as P2 based on the variant meeting the following ACMG Criteria: PS2,PM2,PP3,PP1,PP2. -

Jun 12, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32724172). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.54). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FGFR1 related disorder (ClinVar ID: VCV000050849 /PMID: 20536592). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23643382, 25497574, 32724172). A different missense change at the same codon (p.Gly348Glu) has been reported to be associated with FGFR1 related disorder (ClinVar ID: VCV000974813 /PMID: 26199944). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

FGFR1-related disorder Pathogenic:2

Oct 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FGFR1 c.1042G>A (p.Gly348Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249898 control chromosomes. c.1042G>A has been reported in the literature in individuals affected with autosomal dominant congenital hypogonadotropic hypogonadism and Kallmann syndrome, including at-least two de novo occurences (example, Acierno_2020, Zhang_2021, BailleulForestier_2010). These data indicate that the variant is very likely associated with FGFR1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished response of fibroblast growth factor 8 stimulation (Acierno_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32724172, 34348883, 20536592). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGFR1 c.1042G>A variant is predicted to result in the amino acid substitution p.Gly348Arg. This variant has been reported in many individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Bailleul-Forestier et al. 2010. PubMed ID: 20536592; Table S3, Miraoui et al. 2013. PubMed ID: 23643382; Table S2, Cassatella et al. 2018. PubMed ID: 29419413; Acierno et al. 2020. PubMed ID: 32724172). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Apr 15, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect through an inability to induce luciferase activity (PMID: 32724172); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23643382, 25394172, 20536592, 25497574, 34758253, 29419413, 36531499, 34348883, 32724172) -

Hypogonadotropic hypogonadism 2 with anosmia Other:1

Aug 01, 2015

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;.;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D
Vest4		0.97
MutPred		0.75		.;.;Loss of catalytic residue at S350 (P = 0.0895);Loss of catalytic residue at S350 (P = 0.0895);.;.;.;.;.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886037634; hg19: chr8-38279354; COSMIC: COSV100248113; COSMIC: COSV100248113;