ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1190C>T (p.Ser397Leu) (rs773134475)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716033 SCV000846866 likely pathogenic History of neurodevelopmental disorder 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 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 397 of the DHCR7 protein (p.Ser397Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs773134475, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with Smith-Lemli-Opitz Syndrome (PMID: 15521979, 23293579, 22211794, 10677299). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
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.

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