Structural eye disease

Gene: C16orf62

I don't know

Comment on list classification: There are now 5 unrelated probands reported in literature with biallelic VPS35L (old name C16orf62) variants, and Ritscher-Schinzel syndrome. Both missense and nonsense variants have been reported. Of 5 probands, 3 were noted to have eye anomalies: one with coloboma & microphthalmia, and 2 probands with glaucoma. Based on the variable phenotype, this gene should remain Amber on Structural eye disease, until more evidence emerges.

Created: 23 Oct 2026, 3:29 p.m. | Last Modified: 23 Oct 2026, 3:29 p.m.

Panel Version: 5.8

PMID: 42144185 Carelli et al., 2026
Case report of a North African male infant with Ritscher-Schinzel syndrome, harbouring a homozygous VPS35L variant (NM_020314.7: c.881T > C; p.(Phe294Ser)). Method: Trio WES. Proband presented with failure to thrive, with a weight of 2020 g (−2.9 SDS), length of 45 cm (−7.8 SDS), and head circumference of 31 cm (−7.5 SDS). He also had facial dysmorphism, severe axial hypotonia, limb anomalies including bilateral ulnar deviation of the fingers, splenomegaly, suspected unilateral cryptorchidism. Brain MRI showed multiple anomalies, particularly cerebellar and cortical dysplasia. No evident neurodevelopmental delay at 14 months. Trio exome detected a homozygous VPS35L variant NM_020314.7:c.881T > C; p.(Phe294Ser) in the proband, parents confirmed het.

PMID: 36113987 Otsuji et al., 2023
Reported 3 unrelated patients with biallelic VPS35L variants. Overlapping clinical features included GDD, ID (mild in 2 individuals and profound in 1), short stature (short stature between −2 and −3 SD in 2 probands, and -6 SD in one), brain anomalies on imaging, craniofacial dysmorphism, ophthalmological malformation (glaucoma in 2/3), skeletal complications (Brachymelia/Brachydactyly in 2 probands and reduced distal creases in 3), and cryptorchidism. 2 probands had biallelic nonsense variants, while the third proband, most severely affected, was homozygous for a missense variant VPS35L: p.P876L.

PMID: 31712251 Kato et al., 2020
Report of 2 sibs with Ritscher-Schinzel syndrome and compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs*28 and c.2755G>A; p.Ala919Thr) in VPS35L. The individuals presented with cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation.

VPS35L is associated with AR Ritscher-Schinzel syndrome 3, OMIM:619135 (OMIM accessed 23rd Oct 2026).

Created: 23 Oct 2026, 3:13 p.m. | Last Modified: 23 Oct 2026, 3:13 p.m.

Panel Version: 5.8

Comment on phenotypes: OMIM phenotype added 1st May 2026.

Created: 1 May 2026, 2:47 p.m. | Last Modified: 1 May 2026, 2:47 p.m.

Panel Version: 4.44

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ritscher-Schinzel syndrome 3, OMIM:619135; Ritscher-Schinzel syndrome 3, MONDO:0030864

Publications

• 31712251
• 36113987
• 42144185

I don't know

Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251).

Created: 8 Jun 2020, 11:16 a.m. | Last Modified: 8 Jun 2020, 11:16 a.m.

Panel Version: 1.7

The HGNC approved name for this gene is: VPS35 endosomal protein sorting factor like (VPS35L)
Sources: Literature

Created: 8 Jun 2020, 11:14 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
3C/Ritscher-Schinzel-like syndrome

Publications

• 31712251