Structural eye disease

Gene: GDF3

Red List (low evidence)

p.Arg266Cys is present in >4,000 individuals in gnomad v4, casting serious doubts about pathogenicity.

p.Arg195Gln is present in 239 individuals which is also very high even for 'variable penetrance'.

p.Arg274Trp is present in 156.

p.Leu305Pro in 349. Also classified 'benign' in ClinVar.

p.Pro325Leu in 77.

Created: 3 Nov 2023, 7 a.m. | Last Modified: 3 Nov 2023, 7:05 a.m.

Panel Version: 3.56

I don't know

A total of five GDF3 variants have been reported in PMID: 19864492, 24281366 & 29260090 in patients with ocular phenotypes. It has been noted, that some of the variants have been found in gnomAD v4.0.0 at a high frequency and in unaffected relatives of the patients. A summary of the allele frequencies and other information is presented below.
NM_020634.3(GDF3):c.796C>T (p.Arg266Cys)
• rs140926412
• https://gnomad.broadinstitute.org/variant/12-7690177-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 4046/1614130 = allele frequency of 0.002507 which could be considered as scoring BS1 depending on the frequency of the disease
• PMID: 19864492; 29260090
NM_020634.3(GDF3):c.584G>A (p.Arg195Gln)
• rs146973734
• https://gnomad.broadinstitute.org/variant/12-7690389-C-T?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 239/1614062 = allele frequency 0.0001481 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia
NM_020634.3(GDF3):c.820C>T (p.Arg274Trp)
• rs387906946
• https://gnomad.broadinstitute.org/variant/12-7690153-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 156/1614148 = allele frequency 0.00009665 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 19864492 one patient with Unilateral microphthalmia and coloboma
NM_020634.3(GDF3):c.914T>C (p.Leu305Pro)
• rs387906945
• https://gnomad.broadinstitute.org/variant/12-7690059-A-G?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 349/1614130 = allele frequency 0.0002162 which could be considered slightly too frequent to score PM2 depending on the frequency of the disease
• PMID: 19864492 three cases:
o 1 patient (2.1) with Unilateral microphthalmia and incomplete penetrance.
o 1 patient (2.2) unaffected father of 2.1
o 1 patient with Bilateral iris coloboma
NM_020634.3(GDF3):c.974C>T (p.Pro325Leu)
• rs566697767
• https://gnomad.broadinstitute.org/variant/12-7689999-G-A?dataset=gnomad_r4
• gnomAD v4.0.0 exomes & genomes: 77/1613890 = allele frequency 0.00004771 which could be considered as scoring PM2 depending on the frequency of the disease
• PMID: 24281366
o 1 patient 11 with microphthalmia and coloboma, also compound heterozygote for two missense mutations in CYP1B1, c.1103G>A, p.(Arg368His), and c.685G>A, p.(Glu229Lys), which is associated with ocular phenotypes (OMIM: 231300 & OMIM: 617315) and is Green on Structural eye disease panel
o 1 patient unaffected father of the patient above

As a result of this analysis, it seems unlikely that c.796C>T (p.Arg266Cys) is disease causing, due to its high frequency in gnomAD v4.0.0. The contribution of c.974C>T (p.Pro325Leu) to the disease is unknown, as it has only been seen in a patient who was also compound heterozygous for CYP1B1 variants. Plus, c.974C>T (p.Pro325Leu) was also seen in the unaffected father of the patient, as was c.914T>C (p.Leu305Pro); leading to the assertion that the effects of GDF3 variants of is subject to reduced penetrance. The variants c.584G>A (p.Arg195Gln) and c.820C>T (p.Arg274Trp) were found at low frequency in gnomAD v4.0.0. and there were no reports of unaffected carriers of these variants in the cited publications.

Created: 16 Nov 2023, 5:56 p.m. | Last Modified: 16 Nov 2023, 6:04 p.m.

Panel Version: 3.57

I don't know

PMID: 29260090 reported a patient with microphthalmia and the same p.Arg266Cys variant reported in multiple patients before. Unaffected mother was a carrier

Created: 15 Sep 2023, 12:54 p.m. | Last Modified: 15 Sep 2023, 12:54 p.m.

Panel Version: 3.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Klippel-Feil Syndrome 3; Klippel-Feil syndrome 3, autosomal dominant; Microphthalmia with coloboma 6; Microphthalmia, isolated

Publications

• 29260090

I don't know

Ye reported at least five families with microphthalmia or coloboma, incomplete penetrance was observed

Created: 19 Jun 2019, 3:32 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Klippel-Feil Syndrome3; Microphthalmia with coloboma 6; Microphthalmia, isolated 7; 613702; 613703; 613704

Publications

• 19864492

Mode of pathogenicity
other - please provide details in the comments

I don't know

Promoted from red to amber based on the expert review provided.

Created: 25 Apr 2019, 10:04 a.m.

Submitted on behalf of Professor Nicola Ragge (Wessex and West Midlands GLH). Ye reported at least five families with microphthalmia or coloboma, incomplete penetrance was observed

Created: 17 Apr 2019, 3:30 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Klippel-Feil Syndrome3, 613702; Microphthalmia with coloboma 6, 613703; Microphthalmia, isolated 7, 613704

Publications

• 19864492

Mode of pathogenicity
Other - please provide details in the comments