Submissions for variant NM_014956.5(CEP164):c.3001C>G (p.Leu1001Val)

gnomAD frequency: 0.00043  dbSNP: rs199637319

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493085	SCV000582228	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing	The L1001V variant in the CEP164 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L1001V variant is observed in 25/66,380 (0.04%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The L1001V 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 where amino acids with similar properties to Leucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret L1001V as a variant of uncertain significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625376	SCV000745139	uncertain significance	Nephronophthisis 15	2016-03-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000625376	SCV000896129	uncertain significance	Nephronophthisis 15	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625376	SCV001230056	uncertain significance	Nephronophthisis 15	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1001 of the CEP164 protein (p.Leu1001Val). This variant is present in population databases (rs199637319, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CEP164-related conditions. ClinVar contains an entry for this variant (Variation ID: 429616). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CEP164 protein function with a negative predictive value of 80%. 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.
Genetic Services Laboratory, University of Chicago	RCV001821416	SCV002071046	uncertain significance	not specified	2017-11-09	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000493085	SCV005191923	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV000493085	SCV001922677	uncertain significance	not provided		no assertion criteria provided	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816727	SCV005070383	uncertain significance	Retinal dystrophy	2022-01-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752915	SCV005350773	uncertain significance	CEP164-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The CEP164 c.3001C>G variant is predicted to result in the amino acid substitution p.Leu1001Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.