Submissions for variant NM_001360.3(DHCR7):c.199G>A (p.Ala67Thr)

gnomAD frequency: 0.00093  dbSNP: rs143999854

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000681711	SCV000111531	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000681711	SCV000729508	likely benign	not provided	2021-02-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9653161, 28250423, 11241839)
Counsyl	RCV000509217	SCV000799918	uncertain significance	Smith-Lemli-Opitz syndrome	2018-05-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313765	SCV000848313	uncertain significance	Inborn genetic diseases	2022-02-01	criteria provided, single submitter	clinical testing	The c.199G>A (p.A67T) alteration is located in exon 4 (coding exon 2) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 199, causing the alanine (A) at amino acid position 67 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000509217	SCV000933283	likely benign	Smith-Lemli-Opitz syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000509217	SCV001270545	uncertain significance	Smith-Lemli-Opitz syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Revvity Omics, Revvity	RCV000509217	SCV003829082	uncertain significance	Smith-Lemli-Opitz syndrome	2023-08-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415846	SCV004115131	uncertain significance	DHCR7-related disorder	2024-01-03	criteria provided, single submitter	clinical testing	The DHCR7 c.199G>A variant is predicted to result in the amino acid substitution p.Ala67Thr. This variant was reported in a patient with autism spectrum disorder (Table S2, Saskin et al. 2017. PubMed ID: 28250423) and in a patient with tubulointerstitial disease in conjunction with a second pathogenic variant, unknown phase (Table S7, Groopman et al. 2018. PubMed ID: 30586318). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations, with recent classifications split between likely benign and uncertain significance. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000681711	SCV004137204	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987353	SCV004803316	uncertain significance	not specified	2024-01-13	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.199G>A (p.Ala67Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 1612152 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.0011 vs 0.0043), allowing no conclusion about variant significance. c.199G>A has been reported in the literature in unaffected controls and absent from a Smith-Lemli-Opitz Syndrome cohort (e.g. Witsch-Baumgartner_2001), or reported as VUS, benign, or a polymorphism in control individuals without autism (e.g. Saskin_2017, Cross_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. 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: 38027204, 24813812, 28250423, 11241839). ClinVar contains an entry for this variant (Variation ID: 93714). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
New York Genome Center	RCV000509217	SCV005044114	uncertain significance	Smith-Lemli-Opitz syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The inherited c.199G>A (p.Ala67Thr) missense variant identified in the DHCR7 gene has not been reported in individuals with SLOS in the literature, it is reported in an individual with autism (PMID: 28250423) and in a control in a study of patients with SLOS (PMID: 9653161). The variant has 0.0009007 allele frequency in the gnomAD(v3) database (137 out of 152110 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant has been reported in the ClinVar database as variant of uncertain significance (5 submissions) or likely benign (1 submissions) [Variation ID:93714]. The affected residue is not well conserved. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 21.5, REVEL score = 0.469). Based on the available evidence, the inherited c.199G>A (p.Ala67Thr) missense variant identified in the DHCR7 gene is reported as a Variant of Uncertain Significance.
Baylor Genetics	RCV000509217	SCV005049865	uncertain significance	Smith-Lemli-Opitz syndrome	2024-01-26	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000681711	SCV000606908	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Likely Benign and reported on 11-13-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Gharavi Laboratory, Columbia University	RCV000681711	SCV000809164	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research