Submissions for variant NM_181789.4(GLDN):c.1428C>A (p.Phe476Leu)

gnomAD frequency: 0.00003  dbSNP: rs750803388

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000524042	SCV000620893	likely pathogenic	not provided	2017-09-25	criteria provided, single submitter	clinical testing	The F476L variant in the GLDN gene has been reported previously in the compound heterozygous state with a second GLDN variant in an infant with arthrogryposis multiplex congenita (Wambach et al., 2017). The F476L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The F476L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret F476L as a likely pathogenic variant.
Cirak Lab, University Hospital Cologne	RCV000855464	SCV000996594	likely pathogenic	Fetal akinesia deformation sequence 1; Arthrogryposis multiplex congenita	2019-06-28	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594071	SCV005085888	pathogenic	Lethal congenital contracture syndrome 11	2024-09-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with lethal congenital contracture syndrome 11 (MIM#617194). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated olfactomedin-like domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in two affected individuals, both compound heterozygous with another missense (PMID: 28726266, 31680123). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Protein expression in HeLa cells demonstrated a reduction in cell surface expression (PMID: 32812332) (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_181789.3:c.1507C>T; p.(Gln503*)) in a recessive disease, in an affected individual in this family. (SP) 1206 - This variant has been shown to be paternally inherited (SA path report). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign