ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1228G>A (p.Gly410Ser) (rs80338862)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079640 SCV000233037 pathogenic not provided 2013-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000079640 SCV000564934 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing The G410S variant in the DHCR7 gene has been reported multiple times previously in individuals with Smith-Lemli-Opitz syndrome (SLOS) who had a second DHCR7 variant identified (Fitzky et al., 1998; Scalco et al., 2005; Kolejakova et al., 2009). Expression studies in a human cell line found that G410S reduced DHCR7 protein expression by greater than 90% compared to wild-type (Fitzky et al., 1998). The G410S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G410S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and a different missense variant in the same residue (G410R) as well as missense variants in nearby residues (H405Y, N407Y, Y408H, D411N) have been reported in the Human Gene Mutation Database in association with SLOS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, G410S variant is considered to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000020434 SCV000697851 pathogenic Smith-Lemli-Opitz syndrome 2017-05-04 criteria provided, single submitter clinical testing Variant summary: The DHCR7 c.1228G>A (p.Gly410Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.000043 (5/116304 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). In the literature, the variant has been identified in several patients with SLOS in compound heterozygous state with other pathogenic/likely pathogenic mutations as well as in homozygous state (e.g., Kolejakova_Gen Physiol Biophys_2009; Kalb_Clin Genet_2012). Cell-based functional studies have been performed that revealed a severe reduction in protein expression and enzyme activity due to the variant (Fitzky_PNAS_1998; Shim_BBRC_2004). The variant also lies at one of the transmembrane regions of the protein, where many known pathogenic mutations are located (Fitzky_PNAS_1998). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000020434 SCV000832368 pathogenic Smith-Lemli-Opitz syndrome 2019-06-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 410 of the DHCR7 protein (p.Gly410Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs80338862, ExAC 0.03%). This variant has been observed to be homozygous or in combination with another DHCR7 variant in individuals affected with Smith-Lemli-Opitz syndrome (PMID: 9653161, 15896653, 12818773). ClinVar contains an entry for this variant (Variation ID: 21272). This variant has been reported to affect DHCR7 protein function (PMID: 9653161). This variant disrupts the p.Gly410 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been observed in individuals with DHCR7-related conditions (PMID: 10677299), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000720023 SCV000850897 pathogenic History of neurodevelopmental disorder 2017-06-02 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Deficient protein function by in vitro/ex vivo assay;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Baylor Genetics RCV000020434 SCV001163683 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000020434 SCV001193975 pathogenic Smith-Lemli-Opitz syndrome 2019-12-12 criteria provided, single submitter clinical testing NM_001360.2(DHCR7):c.1228G>A(G410S) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 9653161, 15877207, 10896306, 10814720, 15952211, 12818773, 15896653 and 22391996. Classification of NM_001360.2(DHCR7):c.1228G>A(G410S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
GeneReviews RCV000020434 SCV000040847 pathologic Smith-Lemli-Opitz syndrome 2007-10-24 no assertion criteria provided curation Converted during submission to Pathogenic.

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