Submissions for variant NM_001160148.2(DDHD1):c.2299C>T (p.Arg767Cys)

dbSNP: rs1057518484

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414377	SCV000492163	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	The R774C variant in the DDHD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R774C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R774C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R774C as a variant of uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848733	SCV002104588	uncertain significance	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002521427	SCV003495035	uncertain significance	Hereditary spastic paraplegia 28	2023-05-12	criteria provided, single submitter	clinical testing	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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 774 of the DDHD1 protein (p.Arg774Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DDHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373562). 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 DDHD1 protein function.