Submissions for variant NM_001360.3(DHCR7):c.740C>T (p.Ala247Val)

dbSNP: rs886041354

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000383910	SCV000329857	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 10995508, 9653161, 15464432, 11111101, 23293579, 15670717, 11175299, 10677299, 24500076, 23042628, 12914579)
Counsyl	RCV000670451	SCV000795305	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000670451	SCV001163700	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670451	SCV001203581	pathogenic	Smith-Lemli-Opitz syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the DHCR7 protein (p.Ala247Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 9653161, 10995508, 15896653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 280065). 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%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000670451	SCV002769465	pathogenic	Smith-Lemli-Opitz syndrome	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intra and interfamilial variable expressivity (PMID: 35305950). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ergosterol biosynthesis ERG4/ERG24 family domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Ala247Ser) and p.(Ala247Thr) have been classified as likely pathogenic and pathogenic respectively by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has also been observed as compound heterozygous in several individuals with Smith-Lemli-Opitz syndrome in the literature (PMIDs: 10995508, 10677299, 23293579, 9653161). (SP) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. Markedly increased 7-dehydrocholesterol levels have been observed in a blood sample of this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000670451	SCV005629861	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-03-22	criteria provided, single submitter	clinical testing