Submissions for variant NM_001360.3(DHCR7):c.89G>C (p.Gly30Ala)

gnomAD frequency: 0.00006  dbSNP: rs200334114

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000449598	SCV000537708	pathogenic	Smith-Lemli-Opitz syndrome	2016-09-14	criteria provided, single submitter	clinical testing	This heterozygous missense variant in the DHCR7 gene (autosomal recessive transmission) inherited from the mother was found to be present in combination with a second missense variant in the same gene (compound heterozygosity) in a young female patient with a severe form of ASD
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000449598	SCV000697858	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.89G>C (p.Gly30Ala) 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 6.4e-05 in 251594 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (6.4e-05 vs 0.0043), allowing no conclusion about variant significance. c.89G>C has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Blahakova_2007, Haas_2007, Gabriel_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 23042628, 17497248, 17994283, 34958143). ClinVar contains an entry for this variant (Variation ID: 397518). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000449598	SCV001163343	likely pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000728279	SCV001334465	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	DHCR7: PM3:Very Strong, PM2
GeneDx	RCV000728279	SCV001875088	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	Not observed at a 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: 28250423, 23042628, 17497248, 34958143, 34308104, 17994283, 27535533)
MGZ Medical Genetics Center	RCV000449598	SCV002581309	likely pathogenic	Smith-Lemli-Opitz syndrome	2022-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374732	SCV002685048	likely pathogenic	Inborn genetic diseases	2024-04-03	criteria provided, single submitter	clinical testing	The c.89G>C (p.G30A) alteration is located in exon 3 (coding exon 1) of the DHCR7 gene. This alteration results from a G to C substitution at nucleotide position 89, causing the glycine (G) at amino acid position 30 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.006% (18/282898) total alleles studied. The highest observed frequency was 0.014% (18/129194) of European (non-Finnish) alleles. This variant has been identified in conjunction with another DHCR7 variant in one individual with Smith-Lemli-Opitz confirmed by sterol analysis, in one individual with corpus callosum agenesis and ventriculomegaly, and in the fetus of one pregnant individual with increased 7-DHCR in amniotic fluid (Haas, 2007; Blahakova, 2007; Gabriel, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000449598	SCV003295171	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 30 of the DHCR7 protein (p.Gly30Ala). This variant is present in population databases (rs200334114, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of DHCR7-related conditions (PMID: 17497248, 17994283, 34958143). ClinVar contains an entry for this variant (Variation ID: 397518). 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%. 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.
PreventionGenetics, part of Exact Sciences	RCV003418143	SCV004107058	likely pathogenic	DHCR7-related disorder	2023-05-08	criteria provided, single submitter	clinical testing	The DHCR7 c.89G>C variant is predicted to result in the amino acid substitution p.Gly30Ala. This variant has been reported, along with a second causative variant, in two patients with biochemically diagnosed Smith-Lemli-Opitz syndrome (SLOS) (Haas et al. 2007. PubMed ID: 17497248). It has also been observed along with a second causative variant in a prenatal case with biochemical test results consistent with SLOS (i.e. elevated 7-dehydrocholesterol in the amniotic fluid) (Blahakova et al. 2007. PubMed ID: 17994283). In addition, the c.89G>C variant was identified, along with a nonsense variant in DHCR7 gene, in a fetus with corpus callosum agenesis, and ventriculomegaly (Table S1, Gabriel et al. 2022. PubMed ID: 34958143). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71155910-C-G). This variant is interpreted as likely pathogenic.
Counsyl	RCV000449598	SCV000800521	uncertain significance	Smith-Lemli-Opitz syndrome	2017-05-03	flagged submission	clinical testing
Eurofins Ntd Llc (ga)	RCV000728279	SCV000855832	uncertain significance	not provided	2017-07-25	flagged submission	clinical testing