Variant classification summary

NM_000142.5:c.742C>T

FGFR3 · NP_000133.1:p.(Arg248Cys) · NM_000142.5

GRCh37: chr4:1803564 C>T · GRCh38: chr4:1801837 C>T

Gene: FGFR3 Transcript: NM_000142.5

Final call

Pathogenic

PS3 moderate PS4 strong PM1 moderate PM2 supporting PP3 moderate

Variant details

Gene

FGFR3

Transcript

NM_000142.5

Protein

NP_000133.1:p.(Arg248Cys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 moderate shows significantly increased Arg248Cys FGFR3 dimerization versus wild type.

2

Pathogenic: PS4 strong shows 22/39 affected individuals versus 0/50 controls.

3

Pathogenic: PM1 moderate places Arg248Cys in the significant R248 hotspot.

4

Pathogenic: PM2 supporting shows absence from gnomAD v2.1 and v4.1.

5

Pathogenic: PP3 moderate is supported by REVEL 0.855.

Final determination: Generic ACMG/AMP 2015 rules classify the variant as Pathogenic when 1 strong and 3 moderate pathogenic criteria are satisfied; PM2 supporting is additional 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: the reviewed pathogenic reports document c.742C>T causing p.Arg248Cys, with no established alternate-nucleotide change producing the same amino-acid substitution.	clinvar PMID:25614871 PMID:29593476 spliceai
PS2	Not assessed	Not assessed: no case-level confirmation of both maternity and paternity is documented for an affected proband, despite reports describing sporadic cases.
PS3	Met	Met at moderate strength: FRET measured Arg248Cys K=1110±130 versus 290±60 for wild type, with >10 independent experiments and p<0.001.	PMID:25606676
PS4	Met	Met: 22/39 cases versus 0/50 controls yielded a Haldane-corrected OR 129.86 (95% CI 7.48–2255.60), excluding 1.0 and meeting PS4.	PMID:25614871 PMID:29593476
PM1	Met	Met: p.Arg248Cys lies in a statistically significant R248 hotspot and represented 66.5% of thanatophoric dysplasia type I cases in one registry cohort.	hotspots gnomad_v2 gnomad_v4 PMID:25614871 PMID:29593476
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: FGFR3 p.Arg248Cys is reported in dominant thanatophoric dysplasia, while PM3 is restricted to recessive disorders.	PMID:25614871 PMID:29593476
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 qualifying pathogenic alternate missense change at FGFR3 residue 248 was established in the available comparator evidence.	pm5_candidates PMID:25614871 PMID:29593476
PM6	Not assessed	Not assessed: 16 of 28 TDI patients carried c.742C>T and were called sporadic, but parental testing or a documented de novo assumption is absent.	PMID:29593476
PP1	Not assessed	Not assessed: no multiple affected relatives with documented c.742C>T genotypes are available to demonstrate cosegregation.
PP2	Not assessed	Not assessed: activating FGFR3 missense disease is supported, but no gene-level evidence establishes a low benign-missense rate.	PMID:25614871 gnomad_v2 gnomad_v4
PP3	Met	Met at moderate strength: missense REVEL score 0.855 meets the PP3 threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: no case-specific patient phenotype or family-history information is available to evaluate specificity for a single-gene disease.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for this variant, so ordinary Pathogenic assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no grpmax FAF reaches the BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF above the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: no qualifying healthy adult carrier was reported, and the variant is absent from gnomAD v2.1 and v4.1.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not met	Not met: Arg248Cys showed K=1110±130 versus 290±60 for wild type in a controlled FRET assay, indicating altered function rather than no damaging effect.	PMID:25606676
BS4	Not assessed	Not assessed: no tested affected family members lacking c.742C>T are documented, so lack of segregation cannot be established.
BP1	Not met	Not met: FGFR3 skeletal dysplasia is documented as an activating missense mechanism, with p.Arg248Cys comprising 66.5% of TD I cases.	PMID:25614871 PMID:25606676 PMID:29593476
BP2	Not assessed	Not assessed: available reports confirm heterozygous or sporadic observations but provide no cis/trans relationship with a pathogenic variant.	PMID:25614871 PMID:29593476
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 0.855 is above the BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no case-specific alternate molecular basis for disease is documented for the individual carrying this variant.
BP6	Not met	Not met: ClinVar has no exact-variant benign expert-panel classification and reports zero expert-panel submissions for this variant.	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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