Submissions for variant NM_001360.3(DHCR7):c.292C>T (p.Gln98Ter)

gnomAD frequency: 0.00001  dbSNP: rs104886039

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169020	SCV000220166	likely pathogenic	Smith-Lemli-Opitz syndrome	2014-03-14	criteria provided, single submitter	literature only
GeneDx	RCV000489856	SCV000576842	pathogenic	not provided	2021-09-23	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28166604, 25525159, 15805162, 25405082, 15776424, 15979035, 28349652, 24500076, 21990131, 22929031, 31589614)
Eurofins Ntd Llc (ga)	RCV000489856	SCV000861968	pathogenic	not provided	2018-06-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169020	SCV000893243	pathogenic	Smith-Lemli-Opitz syndrome	2021-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169020	SCV000919259	pathogenic	Smith-Lemli-Opitz syndrome	2018-04-27	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.292C>T (p.Gln98X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was observed with an allele frequency of 3.3e-05 in 274916 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (3.3e-05 vs 0.0043), allowing no conclusion about variant significance. The variant, c.292C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Cardoso_2005, Correa-Cerro_2005, Roullet_2012, Witsch-Baumgartner_2005, Lanthaler_2013, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169020	SCV001163342	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV000169020	SCV001217828	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln98*) in the DHCR7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). This variant is present in population databases (rs104886039, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 15776424, 15805162, 15979035, 22929031). 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: 188723). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV000169020	SCV002093064	pathogenic	Smith-Lemli-Opitz syndrome	2017-05-04	no assertion criteria provided	clinical testing