Submissions for variant NM_005450.6(NOG):c.125C>T (p.Pro42Leu)

dbSNP: rs1018505000

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480013	SCV000568573	uncertain significance	not provided	2017-12-07	criteria provided, single submitter	clinical testing	The P42L variant in the NOG gene has been reported previously in the heterozygous state in a family with variable expressivity of multiple synostosis syndrome. The proband, a five year old male, presented with a bulbous nasal tip with a flat nasal bridge and normal hearing and vision. His hands showed mild hypoplasia of the distal fingers with limited extension, short flat nails and symphalangism of the proximal interphalangeal joints, hypoplasia of the middle phalanges and carpal bone fusion on radiographs. His feet showed pes planovalgus, with short, stiff in motion toes and hypoplastic middle phalanges, talonavicular fusion, osseous fusions of cuneiforms with metatarsals and an absent cuboid bone on radiographs. His affected father had a similar physical and radiographic exam with the addition of a left sided hearing deficit and fusion of the cervical vertebral bodies, intervertebral joints and spinal stenosis. (Lee et al., 2014). The P42L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P42L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (P42T, P42R) have been reported previously in the heterozygous state in individuals with features suggestive of multiple synostosis syndrome (Aydin et al., 2013; Oxley et al., 2008). Missense variants at nearby residues (P37R, L46P, E48K) have been reported in the Human Gene Mutation Database in association with NOG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, this substitution occurs at a position that is not conserved. Therefore, we interpret P42L as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480013	SCV004297487	likely pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with NOG-related symphalangism spectrum disorder (PMID: 25241334; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 42 of the NOG protein (p.Pro42Leu). ClinVar contains an entry for this variant (Variation ID: 420069). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro42 amino acid residue in NOG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18204269, 23732071, 31370824). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.