Variant classification summary

NM_000142.5:c.1118A>G

FGFR3 · NP_000133.1:p.(Tyr373Cys) · NM_000142.5

GRCh37: chr4:1806099 A>G · GRCh38: chr4:1804372 A>G

Gene: FGFR3 Transcript: NM_000142.5

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PM6 moderate PP3 moderate

Variant details

Gene

FGFR3

Transcript

NM_000142.5

Protein

NP_000133.1:p.(Tyr373Cys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong supports damaging gain of function through cellular transformation and concordant skeletal abnormalities in the corresponding mouse model.

2

Pathogenic: PM1 moderate supports the variant because FGFR3 Y373 is a statistically significant mutational hotspot without observed benign population variation.

3

Pathogenic: PM2 supporting supports rarity because the variant is absent from gnomAD v2.1, v4.1, and available non-cancer searches.

4

Pathogenic: PM6 moderate supports the variant because it was validated as de novo in a fetus with lethal skeletal dysplasia without documented parentage confirmation.

5

Pathogenic: PP3 moderate supports a damaging effect because REVEL 0.80 exceeds the calibrated missense threshold.

Final determination: Generic ACMG/AMP 2015 rules classify the variant as Pathogenic when one Strong criterion and three Moderate pathogenic criteria are met; PM2 provides additional supporting evidence.

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	Not met	Not met: available pathogenic reports document the same c.1118A>G nucleotide change, with no alternative nucleotide change producing p.Tyr373Cys.	PMID:19789973 PMID:24476948 clinvar
PS2	Not met	Not met: the variant was validated as de novo in an affected fetus, but confirmation of both maternity and paternity was not documented.	PMID:24476948
PS3	Met	Met, strong: Y373C induced transformation like activating K650E, while corresponding heterozygous mice showed reproducible FGFR3-related skeletal and ossification abnormalities.	PMID:11157491 PMID:23200862 PMID:24419316
PS4	Not assessed	Not assessed: affected cases are reported, but no control counts, odds ratio, or confidence interval are available to test OR >5.0 with CI excluding 1.0.	PMID:19789973 gnomad_v2 gnomad_v4
PM1	Met	Met: FGFR3 Y373 is reported as a statistically significant Cancer Hotspots hotspot, although the partially parsed row requires human confirmation.	hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1, v4.1, and both available non-cancer searches, satisfying the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the exact variant is reported in thanatophoric dysplasia with a de novo occurrence, not a recessive disorder requiring a pathogenic variant in trans.	PMID:24476948 PMID:19789973
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	Not assessed	Not assessed: no validated pathogenic missense comparator at residue Tyr373 was identified for the p.Tyr373Cys variant.	pm5_candidates clinvar
PM6	Met	Met at moderate strength: the exact variant was validated as de novo in a fetus with lethal skeletal dysplasia, without documented maternity and paternity confirmation.	PMID:24476948
PP1	Not assessed	Not assessed: no affected relatives or family segregation data are reported for calculating co-segregation across meioses.
PP2	Not assessed	Not assessed: the bundle lacks a validated gene-wide benign-missense rate and evidence meeting both PP2 requirements.
PP3	Met	Met, moderate: REVEL 0.80 meets the generic PP3 moderate threshold of >=0.773 for this missense variant.	revel
PP4	Not assessed	Not assessed: the case lacks a documented patient phenotype or family history, despite published reports linking the variant to thanatophoric dysplasia.	PMID:19789973
PP5	Not met	Not met: exact-variant ClinVar records are pathogenic, but zero expert-panel submissions are present to satisfy the required PP5 evidence source.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, far below the >=0.05 BA1 stand-alone frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: no population allele frequency was observed in gnomAD v2.1, v4.1, or the non-cancer subsets, so none exceeds 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult carrier, homozygote, or hemizygote observation was documented for this variant.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: Y373C caused cellular transformation and corresponding mice showed disease-relevant skeletal abnormalities, with no neutral functional assay identified.	PMID:11157491 PMID:23200862 PMID:24419316
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are reported, so lack of segregation cannot be evaluated.
BP1	Not met	Not met: FGFR3 skeletal dysplasia is documented through activating missense variants, not primarily truncating variants.	PMID:11157491 PMID:23200862 PMID:24419316
BP2	Not assessed	Not assessed: no parental, offspring, or haplotype data establish a pathogenic variant in cis or trans with c.1118A>G.	PMID:24476948
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: REVEL 0.80 exceeds the generic BP4 supporting cutoff of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis is documented for this case, and the available dual-diagnosis report does not verify this exact variant.
BP6	Not met	Not met: ClinVar reports the exact variant as pathogenic and has zero expert-panel submissions supporting a 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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