Submissions for variant NM_001360.3(DHCR7):c.907G>A (p.Gly303Arg)

gnomAD frequency: 0.00014  dbSNP: rs142808899

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724095	SCV000232612	pathogenic	not provided	2017-10-13	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000180217	SCV000267288	uncertain significance	Smith-Lemli-Opitz syndrome	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000180217	SCV000485874	likely pathogenic	Smith-Lemli-Opitz syndrome	2016-02-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000180217	SCV000914537	likely pathogenic	Smith-Lemli-Opitz syndrome	2018-12-13	criteria provided, single submitter	clinical testing	The DHCR7 c.907G>A (p.Gly303Arg) missense variant has been reported in five studies in which it is found in a compound heterozygous state in six individuals with Smith-Lemli-Opitz syndrome (Matsumoto et al. 2005; Ko et al. 2010; Lee et al. 2010; Oh et al. 2014; Tamura et al. 2017). Five of the individuals inherited the variant from one of their unaffected carrier parents; the genotype of the sixth individual's parents is not available. The p.Gly303Arg variant was absent from 184 control chromosomes and is reported at a frequency of 0.00068 in the African American population of the Exome Sequencing Project. The p.Gly303Arg variant is located within the seventh transmembrane domain, which is a highly conserved sterol-sensing domain. Based on the evidence, the p.Gly303Arg variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000180217	SCV000931749	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 303 of the DHCR7 protein (p.Gly303Arg). This variant is present in population databases (rs142808899, gnomAD 0.05%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 16044199, 20052364, 28503313). 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: 198773). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000180217	SCV001163696	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180217	SCV001623341	pathogenic	Smith-Lemli-Opitz syndrome	2021-04-16	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.907G>A (p.Gly303Arg) results in a non-conservative amino acid change located in the seventh transmembrane domain, which represent a highly conserved sterol-sensing domain (Ko_2010, Tamura_2017) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251694 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (9.1e-05 vs 0.0043), allowing no conclusion about variant significance. c.907G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome, Autism spectrum disorder and rare neurodevelopmental disorders (Matsumoto_2005, Ko_2010, Saskin_2017, Tamura_2017, Gao_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=2) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000180217	SCV001752648	pathogenic	Smith-Lemli-Opitz syndrome	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000724095	SCV002513153	likely pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16906538, 27401223, 31178897, 20052364, 28250423, 15521979, 29300326, 23042628, 28503313, 16044199, 33179238, 33836803)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252024	SCV002523524	likely pathogenic	See cases	2020-02-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM2, PM3, PP3
DASA	RCV000180217	SCV002526396	pathogenic	Smith-Lemli-Opitz syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The c.907G>A;p.(Gly303Arg) missense change has been observed in affected individual(s)(PMID: 28503313; 20052364; 16044199; DOI:10.5734/JGM.2014.11.2.86) - PS4. The variant is present at low allele frequencies population databases (rs142808899– gnomAD 0.001249%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Gly303Arg) was detected in trans with a Pathogenic variant (PMID: 28503313; 20052364; 16044199; DOI:10.5734/JGM.2014.11.2.86) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Ambry Genetics	RCV002372105	SCV002688545	pathogenic	Inborn genetic diseases	2017-07-09	criteria provided, single submitter	clinical testing	The p.G303R pathogenic mutation (also known as c.907G>A), located in coding exon 6 of the DHCR7 gene, results from a G to A substitution at nucleotide position 907. The glycine at codon 303 is replaced by arginine, an amino acid with dissimilar properties. This alteration was first confirmed in trans with a recurrent pathogenic alteration in two unrelated individuals of Japanese descent meeting biochemical diagnostic criteria for SLOS (Matsumoto Y et al. J. Hum. Genet., 2005 Jul;50:353-6) and has also been described in trans with other missense alterations in unrelated Japanese and Korean individuals (Tamura M et al. Hum Genome Var, 2017 May;4:17015; Ko JS et al. J. Korean Med. Sci., 2010 Jan;25:159-62). This alteration is located on the alpha helical domain and results in marked domain disruption (Li X et al. Nature, 2015 Jan;517:104-7; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003907631	SCV004725751	pathogenic	DHCR7-related disorder	2024-01-12	criteria provided, single submitter	clinical testing	The DHCR7 c.907G>A variant is predicted to result in the amino acid substitution p.Gly303Arg. This variant has been reported in the compound heterozygous state in individuals with Smith-Lemli-Opitz syndrome (Matsumoto et al. 2005. PubMed ID: 16044199; Ko et al. 2010. PubMed ID: 20052364; Tamura et al. 2017. PubMed ID: 28503313). This variant is reported in 0.050% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.
Biochemistry Laboratory of CDMU, Chengde Medical University	RCV000180217	SCV000899187	pathogenic	Smith-Lemli-Opitz syndrome		no assertion criteria provided	case-control