Submissions for variant NM_000266.4(NDP):c.269G>A (p.Arg90His)

gnomAD frequency: 0.00003  dbSNP: rs104894867

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001306511	SCV001495886	uncertain significance	not provided	2023-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 90 of the NDP protein (p.Arg90His). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg90 amino acid residue in NDP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14635119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDP protein function. ClinVar contains an entry for this variant (Variation ID: 812352). This missense change has been observed in individual(s) with Norrie disease (PMID: 31456290). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375287	SCV001571861	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PM2_Moderate, PM5_Moderate, PP3_Supporting
Laboratoire Génétique Moléculaire, CHRU TOURS	RCV001306511	SCV001760757	benign	not provided	2019-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001306511	SCV002504561	likely benign	not provided	2019-10-31	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003091	SCV001161152	likely pathogenic	Atrophia bulborum hereditaria	2019-06-23	no assertion criteria provided	research