Submissions for variant NM_001360.3(DHCR7):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00004  dbSNP: rs104886033

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169384	SCV000220774	likely pathogenic	Smith-Lemli-Opitz syndrome	2014-10-07	criteria provided, single submitter	literature only
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224026	SCV000280787	pathogenic	not provided	2015-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000224026	SCV000568697	likely pathogenic	not provided	2023-11-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15776424, 31589614, 9634533, 15952211, 12949967, 16983147, 22391996, 24500076, 21990131)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169384	SCV000697854	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-07-20	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121390 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant has been reported in multiple compound heterozygous SLOS patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. The variant of interest affects the translational start sight, however, Scalco_2005 indicates that translational initiation at Methionine 59 produces a functional protein. Therefore, suggesting that this would help explain the mild phenotype observed in affected individuals. Taken together, this variant is classified as likely pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000169384	SCV000923648	pathogenic	Smith-Lemli-Opitz syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000169384	SCV000999307	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169384	SCV001163344	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV000169384	SCV001236046	pathogenic	Smith-Lemli-Opitz syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 12949967, 15776424, 15952211, 16983147, 21990131). ClinVar contains an entry for this variant (Variation ID: 6794). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001267308	SCV001445489	pathogenic	Inborn genetic diseases	2020-06-01	criteria provided, single submitter	clinical testing	The alteration results in an initiation codon change: _x000D_ _x000D_ The c.1A>G (p.M1?) alteration is located in exon 3 (coding exon 1) of the DHCR7 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon (ATG) are typically deleterious in nature as they are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, there is an in-frame methionine 59 amino acids downstream, which may act as an alternative initiation codon and result in an N-terminal truncation; however, direct evidence is unavailable and the significance of the N-terminus for this protein is not well established. The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1A>G alteration was observed in 0.0014% (4/282880) of total alleles studied, with a frequency of 0.0023% (3/129192) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.1A>G (p.M1?) alteration has been reported in multiple patients with a confirmed biochemical diagnosis of SLOS along with a second disease-causing mutation. Several patients have been reported to have mild clinical symptoms despite co-occuring with a severe allele (Bianconi, 2011; Eroglu, 2017; Scalco, 2005; Witsch-Baumgartner, 2004). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.M1 amino acid is conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic.
Genome-Nilou Lab	RCV000169384	SCV001810394	pathogenic	Smith-Lemli-Opitz syndrome	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169384	SCV002024077	pathogenic	Smith-Lemli-Opitz syndrome	2023-10-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169384	SCV002048412	pathogenic	Smith-Lemli-Opitz syndrome	2020-10-12	criteria provided, single submitter	clinical testing	The DHCR7 c.1A>G; p.Met1? variant (rs104886033) is reported in the literature in multiple individuals affected with Smith-Lemli-Opitz syndrome (SLOS) (Bianconi 2011, Pappu 2006, Scalco 2005, Witsch-Baumgartner 2005). Most affected individuals with this variant were described with mild disease and were found to carry an additional pathogenic variant in trans (Bianconi 2011, Pappu 2006, Scalco 2005, Witsch-Baumgartner 2005). The c.1A>G variant is found on only four chromosomes (4/282880 alleles) in the Genome Aggregation Database. This variant abolishes the canonical start codon, which is likely to negatively impact gene function. While a DHCR7 protein beginning at the next downstream methionine, Met59, has been demonstrated to be enzymatically active (Wassif 2005), it is unknown if this downstream methionine is used in vivo or how the activity compares to the canonical protein. Another variant affecting the canonical methionine (c.3G>A) has also been reported in individuals affected with SLOS and is considered disease-causing (Waterham 2000). Based on available information, the c.1A>G variant is considered to be pathogenic. References: Bianconi SE et al. Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2011 Nov;155A(11):2732-8. Pappu AS et al. Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol. J Lipid Res. 2006 Dec;47(12):2789-98. Scalco FB et al. DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. Am J Med Genet A. 2005 Jul 30;136(3):278-81. Wassif CA et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998 Jul;63(1):55-62. Waterham HR and Wanders RJ. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):340-56. Witsch-Baumgartner M et al. Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. Hum Mutat. 2005 Apr;25(4):412.
Fulgent Genetics, Fulgent Genetics	RCV000169384	SCV002809790	pathogenic	Smith-Lemli-Opitz syndrome	2021-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390651	SCV004121218	likely pathogenic	DHCR7-related disorder	2023-05-15	criteria provided, single submitter	clinical testing	The DHCR7 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant was reported in an individual with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al 2005. PubMed ID: 15776424). This variant is reported on ~0.0028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71155998-T-C). This variant is interpreted as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224026	SCV004226619	pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	PM2, PS1, PS4, PVS1
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000169384	SCV005038863	pathogenic	Smith-Lemli-Opitz syndrome	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000169384	SCV000027392	pathogenic	Smith-Lemli-Opitz syndrome	2005-07-30	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000169384	SCV001469211	pathogenic	Smith-Lemli-Opitz syndrome	2020-05-06	no assertion criteria provided	clinical testing