Classification rationale

PM2PM3PP1PP4 Likely Pathogenic

FGF3 c.310C>T

PM2 (Moderate): ultra-rare population frequency (0.0015% in gnomAD v4.1, zero homozygotes), far below the 0.1% cutoff. PM3 (Moderate): in trans with p.Y49C in an affected compound-heterozygous proband and homozygous in additional affected individuals across two families. PP1 (Supporting): cosegregation with LAMM syndrome in 7 or more affected individuals across 3 unrelated families. PP4 (Supporting): highly specific single-etiology LAMM phenotype (labyrinthine aplasia, microtia, microdontia) in carriers of this exact variant. Combination of 2 moderate + 2 supporting criteria yields Likely Pathogenic under the generic ACMG/AMP 2015 rules.

PM2 + PM3 + PP1 + PP4 → Likely Pathogenic

Gene diagram · NM_005247.2 · variants mapped to exon structure

FGF3 NM_005247.2

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 12 assessed

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

Met (moderate): gnomAD v4.1 allele frequency 0.0015% (zero homozygotes) is far below the 0.1% recessive-disorder cutoff.

gnomad_v2: total AF 2.38588e-05 (0.00239%, 6/251,480 alleles), 0 homozygotes, grpmax FAF 1.121e-05gnomad_v4: total AF 1.48741e-05 (0.00149%, 24/1,613,542 alleles), 0 homozygotes, grpmax FAF 5.818e-05; highest population MID 0.000329924 (0.033%, 2/6,062 alleles) — still below 0.1%gnomad_canada: AF 0.00010866 (0.0109%, 2/18,406 alleles), 0 homozygotes

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:21306635 ↗

✓

PM3 moderate Pathogenic

Met (moderate): the variant is in trans with p.Y49C in an affected compound-heterozygous proband and homozygous in additional affected individuals.

Compound heterozygosity p.R104X (maternal) + p.Y49C (paternal) in an affected LAMM proband, phase confirmed by parental carrier genotypes (PMID:21480479)Homozygous c.310C>T (p.R104X) in all three affected members of family B with heterozygous carrier parents, cosegregating with a fully penetrant autosomal recessive phenotype (PMID:17236138)ACMG/AMP 2015 PM3 rule text: in-trans detection with a pathogenic variant in a recessive disorder = moderate evidence, upgradable to strong with multiple trans observations (PMID:25741868)

PMID:21480479 ↗PMID:17236138 ↗PMID:25741868 ↗

✓

PP1 supporting Pathogenic

Met (supporting): cosegregates with LAMM syndrome, homozygous or compound heterozygous in 7 or more affected individuals across 3 families.

Tekin 2007 family B: 3 affected homozygous c.310C>T, parents heterozygous, unaffected relatives het/wild-typeRiazuddin 2011 family PKDF295: 4 affected homozygous c.310C>T co-segregating with deafness; heterozygous carrier III-3 normalSensi 2011 Patient B: compound heterozygote p.R104X/p.Y49C with maternal p.R104X; both parents unaffected carriers

PMID:17236138 ↗PMID:21306635 ↗PMID:21480479 ↗

✓

PP4 supporting Pathogenic

Met (supporting): the LAMM phenotype (labyrinthine aplasia, microtia, microdontia) is highly specific to biallelic FGF3 mutations and is seen with this exact variant.

Phenotype of 9 affected individuals (microtia, microdontia, profound deafness, Michel aplasia) with homozygous FGF3 mutations including p.R104X (PMID:17236138)Bilateral complete labyrinthine aplasia with microtia/microdontia in p.R104X homozygotes, PKDF295 (PMID:21306635)LAMM phenotype (labyrinthine aplasia, microtia, microdontia) in Patient B with p.R104X compound heterozygosity (PMID:21480479)

PMID:17236138 ↗PMID:21306635 ↗PMID:21480479 ↗clinvar ↗

Assessed · not applied

Pathogenic

PVS1 Not assessed: insufficient evidence was available to score the predicted protein-truncating effect; flagged for human review.

PS3 Not assessed: no well-established functional study of this variant was found in the reviewed literature.

PS4 Not met: affected families and absence from 162 matched controls are qualitative enrichment, not a case-control study with statistical testing.

PP3 Not met: SpliceAI max delta 0.04 is far below the 0.20 splice-altering threshold, and missense predictors do not apply to a stop-gained variant.

Benign

BA1 Not met: the highest population frequency is 0.033% (gnomAD v4.1 Middle Eastern), roughly 30-fold below the >1% BA1 threshold.

BS1 Not met: the highest observed allele frequency (0.033%) is about 9-fold below the >0.3% BS1 cutoff.

BS2 Not met: zero homozygotes in gnomAD v2.1, v4.1, and gnomAD-Canada, and documented homozygotes are all affected with LAMM syndrome.

BS3 Not assessed: no functional study demonstrating retained or normal activity of the truncated protein was available.

BS4 Not met: no affected individual lacks the variant; unaffected relatives are heterozygous carriers or wild-type, as expected for recessive inheritance.

BP2 Not met: the documented in-trans configurations (compound heterozygosity, homozygosity) are evidence of pathogenicity, the opposite of this criterion.

BP4 Not met: a single negative SpliceAI prediction (max delta 0.04) cannot offset the unambiguous protein-truncating consequence of a stop-gained variant.

BP5 Not assessed: insufficient data were available to determine whether an alternate molecular basis of disease existed in affected cases.

N/A · 12 PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.48741e-05; MAF= 0.00149%, 24/1613542 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 5.818e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.38588e-05; MAF= 0.00239%, 6/251480 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 6.53253e-05; MAF= 0.00653%, 2/30616 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010866021949364337, 2/18406 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0015% · 24 / 1,613,542
0 hom · FAF 0.0058%

Middle Eastern 2 / 6,062	0.033%
African/African American 5 / 75,014	0.0067%
South Asian 3 / 91,062	0.0033%
European (non-Finnish) 14 / 1,179,496	0.0012%

+ 6 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0024% · 6 / 251,480
0 hom · FAF 0.0011%

South Asian 2 / 30,616	0.0065%
European (non-Finnish) 4 / 113,766	0.0035%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

0.011% · 2 / 18,406
0 hom · FAF 0.003%

European (non-Finnish)

2 / 11,728

0.017%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories). (ClinVarID = 13838)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.66.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100490202, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

4papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & References.

Homozygous mutations in fibroblast growth factor 3 are associated with a new form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia.

PMID 17236138 ↗ · Tekin M et al. · 2007 Feb CLINVAR · case observation

Searched

c.310C>Tp.Arg104Terp.R104Xsegregationparents

Found

Original report of FGF3 mutations in LAMM syndrome. In Turkish family B, the nonsense mutation c.310C>T (p.R104X) is homozygous in all three affected members; all available parents are heterozygous carriers and unaffected relatives are heterozygous or homozygous wild-type (pedigree fig. 1). Segregation is fully consistent with completely penetrant autosomal recessive inheritance, confirming the variant is inherited (not de novo). Family A (p.S156P) and family C (p.V206SfsX117) carry different mutations and are not directly relevant to this variant. Note: the extracted OCR text renders the transition as 'c.310CrT' where 'r' is the OCR artifact for '>'.

Variant

✓ Names this variant — characterised directly

Applied to

→PM2 moderate

Documents p.R104X exclusively as a rare fully penetrant recessive disease allele observed only in affected families; no population or control cohort frequency reported, consistent with PM2 met.

→PM3 moderate

Three affected probands homozygous for the variant (biallelic, variant in trans with itself) with heterozygous carrier parents in a fully penetrant autosomal recessive disorder; supports biallelic involvement and may be counted toward PM3 strength if homozygous observations are accepted as trans evidence.

→PP1 supporting

c.310C>T homozygous in all 3 affected members of family B with both parents heterozygous carriers and unaffected relatives het/wild-type - cosegregation consistent with autosomal recessive LAMM

→PP4 supporting

Documents the highly specific phenotype (microtia, microdontia, profound deafness, Michel aplasia) in individuals homozygous for this exact variant, supporting phenotype specificity for a single genetic etiology

We found a nonsense homozygous mutation, c.310CrT (p.R104X), in the second exon of FGF3 in all three of the affected members of family B (fig. 7). All available parents were heterozygous, and unaffected relatives were heterozygous or homozygous for the wild-type allele in this family (fig. 1).

Location Results section, Family B paragraph; Figure 1 (pedigrees of three Turkish families); Figure 7 (mutation electropherograms) · Context Three unrelated Turkish families with autosomal recessive syndromic deafness (Michel aplasia, microtia, microdontia); homozygosity mapping with 10K SNP arrays followed by Sanger sequencing of FGF3 exons in all available family members; mutations screened in 300 healthy Turkish controls · full text

Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome.

PMID 21306635 ↗ · Riazuddin S et al. · 2011 Feb 9 CLINVAR · case observation

Searched

c.310C>Tp.R104Xp.Arg104Tersegregationcarriers

Found

Prospective molecular genetic study of Pakistani families segregating deafness linked to the DFNB63 locus on 11q13. Family PKDF295 segregates homozygous c.310C>T (p.R104X) in four affected members (IV:1, IV:2, IV:7, IV:8) with complete labyrinthine aplasia; the mutation was previously reported and was not found in 162 ethnically matched normal-hearing controls. A heterozygous carrier (III-3, PKDF295) showed no abnormal temporal bone findings on imaging, consistent with recessive carrier status. This adds a second family (4 affected homozygotes) with cosegregation of the variant with disease.

Variant

✓ Names this variant — characterised directly

Applied to

→PM2 moderate

Absence of p.R104X from 162 matched Pakistani normal-hearing controls directly supports PM2 (low/absent population frequency).

→PM3 moderate

→PP1 supporting

c.310C>T homozygous in 4 affected members of family PKDF295 co-segregating with deafness; heterozygous carrier III-3 clinically and radiologically normal - additional recessive cosegregation for PP1

→PP4 supporting

Documents bilateral complete labyrinthine aplasia with microtia/microdontia in p.R104X homozygotes, supporting the highly specific LAMM phenotype

One mutation (p.R132GfsX26 (c.394delC) from family PKDF887) was novel and the other two mutations (p.R95W (c.283 C > T) from PKDF817 and p.R104X (c.310C > T) from PKDF295) were previously reported (Table 1 ; Figure 1 )

Location Results ('FGF3 mutations in DFNB63-linked families'); Table 1 (family PKDF295 rows IV:1, IV:2, IV:7, IV:8); temporal bone imaging paragraph on heterozygous carriers · Context Five Pakistani families linked to DFNB63 locus; homozygosity mapping and FGF3 sequencing; 162 ethnically matched Pakistani normal-hearing controls; temporal bone CT/3D-FIESTA MRI in 10 affected and 3 heterozygous individuals · full text

LAMM syndrome with middle ear dysplasia associated with compound heterozygosity for FGF3 mutations.

PMID 21480479 ↗ · Sensi A et al. · 2011 May CLINVAR · case observation

Searched

c.310C>Tp.R104Xp.Arg104Tercompound heterozygosityparents

Found

First report of FGF3 compound heterozygotes in two European non-consanguineous families. Patient B (Italian) carries the paternal missense p.Y49C in compound heterozygosity with the maternal nonsense p.R104X (c.310C>T), confirming maternal transmission of the variant in a third independent family; both parents are normal-hearing, unaffected carriers. The heterozygous mother had surgically corrected unilateral microtia without hearing loss or dental findings, discussed by the authors as possibly related to heterozygosity but not constituting non-segregation. Family A carries different mutations (p.Y106C/p.W153VfsX51) and is not relevant to this variant.

Variant

✓ Names this variant — characterised directly

Applied to

→PM2 moderate

Recurrent p.R104X observed only in affected patients across families; control screening (50 European controls) supports rarity of FGF3 mutations, though it covered the new missense variants rather than p.R104X itself.

→PM3 moderate

Variant p.R104X detected in trans with p.Y49C in an affected LAMM proband; phase confirmed by parental carrier genotypes (maternal p.R104X, paternal p.Y49C) — direct PM3 evidence for an autosomal recessive disorder.

→PP1 supporting

Patient B affected with biallelic FGF3 mutations including maternal p.R104X; both parents unaffected heterozygous carriers - additional family segregating the variant with disease in the recessive model

→PP4 supporting

Confirms p.R104X in a patient with the highly specific LAMM phenotype (labyrinthine aplasia, microtia, microdontia)

In Patient B the paternal missense mutation p.Y49C was found in compound heterozygosity with the maternal nonsense mutation (p.R104X).

Location Results section, Patient B (Italian family); Discussion paragraph on the heterozygous mother's unilateral microtia · Context Two European families from non-consanguineous marriages with LAMM syndrome; FGF3 Sanger sequencing of propositi and parents (NM_005247.2); 50 unrelated European control subjects (100 chromosomes) tested for the novel missense variants · full text

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

22993869 ↗ Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia. CLINVAR