Submissions for variant NM_001360.3(DHCR7):c.376G>A (p.Val126Ile)

gnomAD frequency: 0.00030  dbSNP: rs143587828

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178841	SCV000231006	uncertain significance	not provided	2018-04-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000297594	SCV000373923	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.
Ambry Genetics	RCV002314649	SCV000848705	uncertain significance	Inborn genetic diseases	2023-10-05	criteria provided, single submitter	clinical testing	The c.376G>A (p.V126I) alteration is located in exon 5 (coding exon 3) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the valine (V) at amino acid position 126 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mendelics	RCV000178841	SCV001135033	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000297594	SCV001520020	uncertain significance	Smith-Lemli-Opitz syndrome	2020-04-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000178841	SCV001776810	uncertain significance	not provided	2025-02-03	criteria provided, single submitter	clinical testing	Variant identified in a patient with autism; however, it is unclear whether a second variant in this gene was identified (PMID: 28250423); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in homozygous state in an adult with normal serum cholesterol and no reported features of SLOS (PMID: 34168679); This variant is associated with the following publications: (PMID: 31130284, 28250423, 24813812, 29300326, 34168679)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000297594	SCV002512350	uncertain significance	Smith-Lemli-Opitz syndrome	2021-02-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV000297594	SCV003796124	likely benign	Smith-Lemli-Opitz syndrome	2024-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488428	SCV004241064	uncertain significance	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.376G>A (p.Val126Ile) results in a 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 0.00012 in 250706 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00012 vs 0.0043), allowing no conclusion about variant significance. c.376G>A has been reported in the literature in a homozygous 12 months old dysmorphic male with microcephaly, and strabismus (example: Monies_2019). These data indicate that the variant may be associated with disease. 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: 34168679, 24813812, 31130284, 28250423). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000297594	SCV004804895	uncertain significance	Smith-Lemli-Opitz syndrome	2024-03-17	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000297594	SCV005629887	uncertain significance	Smith-Lemli-Opitz syndrome	2024-03-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000297594	SCV001459049	uncertain significance	Smith-Lemli-Opitz syndrome	2018-06-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748637	SCV005351335	uncertain significance	DHCR7-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The DHCR7 c.376G>A variant is predicted to result in the amino acid substitution p.Val126Ile. This variant was reported in individuals with Smith-Lemli-Opitz syndrome (Cross et al. 2015. PubMed ID: 24813812; Saskin et al. 2017. PubMed ID: 28250423; Monies et al. 2019. PubMed ID: 31130284; Alharazy et al. 2021. PubMed ID: 34168679). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.