ClinVar Miner

Submissions for variant NM_004773.4(ZNHIT3):c.92C>T (p.Ser31Leu) (rs148890852)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group, Broad Institute RCV000490627 SCV001430796 likely pathogenic PEHO syndrome 2020-05-29 criteria provided, single submitter research The heterozygous p.Ser31Leu variant in ZNHIT3 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in an individual with PEHO syndrome (PMID: 31048081). This variant has also been reported in 22 additional individuals with PEHO syndrome, segregated with disease in 4 affected relatives from 2 families (PMID: 28335020), which increases the likelihood that the p.Ser31Leu variant is pathogenic. The variant has also been reported as pathogenic by OMIM in ClinVar (Variation ID: 427725). The p.Ser31Leu variant has been identified in 0.476% (119/25006) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148890852). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ser31Leu is located in a region of ZNHIT3 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28335020). Additionally, animal models in zebrafish and in vitro functional studies have shown that this variant causes PEHO syndrome (PMID: 28335020). However, these types of experiments may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PM1_Supporting, PP1 (Richards 2015).
OMIM RCV000490627 SCV000579317 pathogenic PEHO syndrome 2017-06-01 no assertion criteria provided literature only

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