Submissions for variant NM_001360.3(DHCR7):c.1190C>T (p.Ser397Leu)

dbSNP: rs773134475

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002312433	SCV000846866	likely pathogenic	Inborn genetic diseases	2016-06-20	criteria provided, single submitter	clinical testing	The p.S397L variant (also known as c.1190C>T), located in coding exon 7 of the DHCR7 gene, results from a C to T substitution at nucleotide position 1190. The serine at codon 397 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in multiple patients with Smith-Lemli-Opitz Syndrome, who also carried pathogenic mutations in DHCR7 (Witsch-Baumgartner M et al, Am. J. Hum. Genet. 2000 Feb; 66(2):402-12; Ciara E et al, Clin. Genet. 2004 Dec; 66(6):517-24; Balogh I et al, Mol Syndromol 2012 Nov; 3(5):215-22; Kalb S et al, Clin. Genet. 2012 Jun; 81(6):598-601). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6487 samples (12974 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000805883	SCV000945858	pathogenic	Smith-Lemli-Opitz syndrome	2023-04-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Smith-Lemli-Opitz Syndrome (PMID: 10677299, 15521979, 22211794, 23293579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs773134475, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 397 of the DHCR7 protein (p.Ser397Leu). ClinVar contains an entry for this variant (Variation ID: 587952). For these reasons, this variant has been classified as Pathogenic. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000805883	SCV001572512	likely pathogenic	Smith-Lemli-Opitz syndrome	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.1190C>T (p.Ser397Leu) results in a non-conservative amino acid change located in the fourth cytoplasmic loop domain of 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 1.2e-05 in 241462 control chromosomes. c.1190C>T has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome and subsequently cited by others (example, Witsch-Baumgartner_2000, Ciara_2004, Kalb_2012, Balogh_2012, Donoghue_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
3billion	RCV000805883	SCV002521597	pathogenic	Smith-Lemli-Opitz syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000587952). The variant has been reported to be in trans with pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 15521979, 22211794, 23293579). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000805883	SCV003828884	likely pathogenic	Smith-Lemli-Opitz syndrome	2022-02-17	criteria provided, single submitter	clinical testing