Variant classification summary

NM_000142.5:c.1138G>A

FGFR3 · NP_000133.1:p.(Gly380Arg) · NM_000142.5

GRCh37: chr4:1806119 G>A · GRCh38: chr4:1804392 G>A

Gene: FGFR3 Transcript: NM_000142.5

Final call

Pathogenic

PS1 strong PS3 strong PM1 moderate PM2 supporting PM5 moderate PM6 moderate PP3 supporting

Variant details

Gene

FGFR3

Transcript

NM_000142.5

Protein

NP_000133.1:p.(Gly380Arg)

gnomAD AF

4.339309181978229e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong because c.1138G>C produces the same p.Gly380Arg substitution.

2

Pathogenic: PS3 strong because three orthogonal assays showed constitutive FGFR3 activation and abnormal cellular or receptor behavior.

3

Pathogenic: PM1 moderate because codon 380 is a significant FGFR3 hotspot in the transmembrane domain.

4

Pathogenic: PM2 supporting because gnomAD v4.1 AF is 4.33931e-06 and v2.1 is absent.

5

Pathogenic: PM5 moderate because p.Gly380Lys was reported as pathogenic at the same residue.

6

Pathogenic: PM6 moderate because the variant was absent from both unaffected parents without confirmed parentage.

7

Pathogenic: PP3 supporting because REVEL is 0.696, above the 0.644 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria satisfy the Pathogenic classification rule; the additional moderate and supporting criteria are concordant.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met: c.1138G>C and c.1138G>A both produce the established pathogenic FGFR3 p.Gly380Arg substitution at codon 380.	PMID:17256796
PS2	Not met	Not met: the variant was absent from both parents, but maternity and paternity confirmation was not documented as required for PS2.	PMID:16411219
PS3	Met	Met, strong: three orthogonal variant-specific assays showed constitutive FGFR3 activation, impaired chondrocyte function, and altered receptor phosphorylation or heterodimerization.	PMID:20624921 PMID:10646125 PMID:21324899
PS4	Not assessed	Not assessed: no verifiable affected-versus-control counts or odds ratio with a 95% confidence interval were available for the exact variant.	PMID:22325359
PM1	Met	Met: FGFR3 codon 380 is a statistically significant hotspot, and approximately 98% of achondroplasia cases involve nucleotide 1138.	hotspots PMID:12461689
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 4.33931e-06, below the <=0.0001 PM2 threshold, and v2.1 is absent.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: achondroplasia is a heterozygous FGFR3 disorder, whereas PM3 applies only to recessive disorders with an in-trans pathogenic variant.	PMID:21324899 PMID:16411219
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Met	Met: the pathogenic alternate missense p.Gly380Lys was reported at the same residue as p.Gly380Arg in a hypochondroplasia family.	PMID:17256796
PM6	Met	Met at moderate: c.1138G>A was absent from both clinically unaffected parents in an affected child, without confirmed maternity and paternity.	PMID:16411219
PP1	Not assessed	Not assessed: no directly verified family segregation data for the exact c.1138G>A variant are available.	PMID:17256796
PP2	Not assessed	Not assessed: FGFR3 missense gain of function is documented, but no gene-level metric establishes a low benign-missense rate.	PMID:17256796 oncokb
PP3	Met	Met at supporting: missense REVEL score 0.696 exceeds the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the case phenotype and family history needed to judge a highly specific achondroplasia presentation were not supplied.
PP5	Not met	Not met: ClinVar has 0 expert-panel submissions, and the pathogenic literature evidence is available for independent review rather than unavailable.	clinvar PMID:12461689
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, far below the >=0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, below the generic >=0.01 BS1 frequency threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD has zero homozygotes, but no observed carrier is documented as a healthy adult for the BS2 requirement.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: exact-variant assays showed increased FGFR3 phosphorylation, constitutive kinase activity, impaired chondrocyte function, and altered receptor heterodimerization.	PMID:20624921 PMID:10646125 PMID:21324899
BS4	Not assessed	Not assessed: unaffected parents were reported, but no affected relative lacking c.1138G>A was documented.	PMID:16411219 PMID:17256796
BP1	Not met	Not met: the documented FGFR3 disease mechanism is activating missense variation, not primarily truncating variation.	PMID:17256796 oncokb
BP2	Not assessed	Not assessed: p.Gly380Arg was in cis with p.Leu377Arg, but the report did not establish the second variant as pathogenic, as BP2 requires.	PMID:16411219
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.696 exceeds the generic BP4 supporting threshold of 0.29.	revel
BP5	Not met	Not met: p.L377R was present in cis, but its additional disease effect was unestablished and p.G380R alone could explain the phenotype.	PMID:16411219
BP6	Not met	Not met: ClinVar shows Pathogenic with 0 expert-panel submissions and no exact-variant expert-panel benign or likely-benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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