Submissions for variant NM_001360.3(DHCR7):c.1349G>A (p.Arg450His)

gnomAD frequency: 0.00010  dbSNP: rs542266962

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674850	SCV000800251	uncertain significance	Smith-Lemli-Opitz syndrome	2018-05-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317913	SCV000849485	uncertain significance	Inborn genetic diseases	2017-05-24	criteria provided, single submitter	clinical testing	The p.R450H variant (also known as c.1349G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide position 1349. The arginine at codon 450 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000674850	SCV001268262	uncertain significance	Smith-Lemli-Opitz syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001556929	SCV001778601	likely pathogenic	not provided	2020-09-02	criteria provided, single submitter	clinical testing	Identified by exome sequencing in one individual from a cohort of patients with autism, however additional clinical information on this patient was not provided and variant was listed as uncertain significance (Saskin et al., 2017).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28250423)
Invitae	RCV000674850	SCV003305469	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-01-29	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 450 of the DHCR7 protein (p.Arg450His). This variant is present in population databases (rs542266962, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Smith-Lemli-Opitz Syndrome (PMID: 10405455, 28250423). ClinVar contains an entry for this variant (Variation ID: 558558). 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) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg450 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226367	SCV003922830	uncertain significance	not specified	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.1349G>A (p.Arg450His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248600 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1349G>A has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.