ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.988G>A (p.Val330Met) (rs139724817)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727172 SCV000568696 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DHCR7 gene. The V330M variant has been reported previously in an individual with suspected Smith-Lemli-Opitz syndrome who had a second DHCR7 variant identified on the other allele; however, this patient's 7-DHC value was significantly lower than the other patients reported in the study (Patrono et al., 2002). The V330M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The V330M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727172 SCV000706341 uncertain significance not provided 2017-12-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763768 SCV000894664 uncertain significance Smith-Lemli-Opitz syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763768 SCV000945627 uncertain significance Smith-Lemli-Opitz syndrome 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 330 of the DHCR7 protein (p.Val330Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs139724817, ExAC 0.08%). This variant has been observed in combination with another DHCR7 variant in an individual affected with Smith Lemli Opitz syndrome (PMID: 12270273). ClinVar contains an entry for this variant (Variation ID: 420113). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001193584 SCV001362511 uncertain significance not specified 2019-07-16 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.988G>A (p.Val330Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 239088 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00036 vs 0.0043), allowing no conclusion about variant significance. c.988G>A has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Patrono_2002) and autism (Saskin_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000763768 SCV001458004 uncertain significance Smith-Lemli-Opitz syndrome 2018-05-11 no assertion criteria provided clinical testing

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