Submissions for variant NM_001360.3(DHCR7):c.3G>A (p.Met1Ile)

gnomAD frequency: 0.00003  dbSNP: rs121909767

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169218	SCV000220478	likely pathogenic	Smith-Lemli-Opitz syndrome	2014-07-07	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169218	SCV001437372	likely pathogenic	Smith-Lemli-Opitz syndrome	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.3G>A (p.Met1?; p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. At-least one report describes evidence supporting alternative translation initiation from the downsteam Methionine codon 59 of the wild-type DHCR7 protein and that the first N-terminal 58 amino acids are not required for enzyme activity apriori (Wassif_1998). Another variant, c.1A>G (p.Met1?, reported as p.Met1Val) has also been reported in a patient with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2005). Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes. c.3G>A has been reported in the literature as a compound heterozygous genotype in at-least three individuals affected with milder clinical manifestations of Smith-Lemli-Opitz Syndrome (example, Waterham_2000, Langius_2003) and has been subsequently cited by others (example, Scalco_2005, Witsch-Baumgartner_2005, Correa-Cerro_2005, Jezela-Stanek_2008). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One clinical diagnostic laboratory has submitted clinical significance assessment as likely pathogenic to ClinVar before 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000169218	SCV001591501	pathogenic	Smith-Lemli-Opitz syndrome	2023-09-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6791). Disruption of the initiator codon has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 12949967). This variant is present in population databases (rs121909767, gnomAD 0.0009%). This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59.
GeneDx	RCV001528227	SCV002818047	likely pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12949967, 11111101, 23042628, 11767235, 11453964)
OMIM	RCV000169218	SCV000027389	pathogenic	Smith-Lemli-Opitz syndrome	2003-09-15	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528227	SCV001739603	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528227	SCV001928910	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001528227	SCV001977743	pathogenic	not provided		no assertion criteria provided	clinical testing