ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.866C>T (p.Thr289Ile) (rs121909765)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412788 SCV000490514 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing The T289I variant in the DHCR7 gene has been reported previously in several individuals with a biochemically confirmed diagnosis of Smith-Lemli-Opitz syndrome who were also heterozygous for a second variant in DHCR7, including two brothers who exhibited developmental and behavioral findings, but only minor physical features of SLOS (Witsch-Baumgartner, et al., 2000; Krakowiak et al., 2000). The T289I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The T289I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret T289I to be a pathogenic variant.
Athena Diagnostics Inc RCV000412788 SCV001143731 likely pathogenic not provided 2019-04-02 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Moderate co-segregation with disease in affected and unaffected individuals, but from a single family.
Baylor Genetics RCV000007191 SCV001163698 pathogenic Smith-Lemli-Opitz syndrome criteria provided, single submitter clinical testing
Invitae RCV000007191 SCV001203505 pathogenic Smith-Lemli-Opitz syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 289 of the DHCR7 protein (p.Thr289Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs121909765, ExAC 0.003%). This variant has been observed to segregate with Smith-Lemli-Opitz syndrome in a family (PMID: 10995508, 11298379). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6789). 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: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007191 SCV000027387 pathogenic Smith-Lemli-Opitz syndrome 2001-04-22 no assertion criteria provided literature only
Counsyl RCV000007191 SCV000486161 likely pathogenic Smith-Lemli-Opitz syndrome 2016-04-06 no assertion criteria provided clinical testing

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