ClinVar Miner

Submissions for variant NM_000188.3(HK1):c.1334C>T (p.Ser445Leu) (rs1064794848)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483739 SCV000570071 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The S445L variant in the HK1 gene has not been published previously as a pathogenic variant nor as a benign variant, to our knowledge. However, GeneDx has observed this variant de novo with confirmed parentage in another individual referred for XomeDx analysis with clinical findings of retinitis pigmentosa. The S445L variant is not observed in large population cohorts (Lek et al., 2016). The S445L 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. We interpret S445L as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000483739 SCV001334615 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001254702 SCV001430769 pathogenic Retinitis pigmentosa 79 2020-05-28 criteria provided, single submitter research The heterozygous p.Ser445Leu variant in HK1 was identified by our study in an individual with neurodevelopmental disorder with visual defects and brain anomalies (PMID: 30778173). Trio exome analysis showed this variant to be de novo, and it was absent from large population studies. This variant has been reported pathogenic by GeneDx and OMIM in ClinVar (Variation ID: 421007). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS2, PM2, PP3, PS4_supporting (Richards 2015).
Ambry Genetics RCV001266687 SCV001444864 likely pathogenic Inborn genetic diseases 2019-09-13 criteria provided, single submitter clinical testing
Department of Genetics,Fundacion Jimenez Diaz University Hospital RCV001270352 SCV001450578 likely pathogenic Retinitis pigmentosa criteria provided, single submitter clinical testing Variant not found in population databases, predicted deleterious by in-silico pathogenicity predictors, reported as pathogenic in ClinVar (VCV000421007.7) , and found to be a de novo variant. (ACMG: PM2 Moderate; PM6: Moderate; PP3 Supporting; PP5: Supporting)
Invitae RCV000483739 SCV001580959 pathogenic not provided 2020-02-07 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 445 of the HK1 protein (p.Ser445Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with retinitis pigmentosa and neurodevelopmental abnormalities (PMID: 30778173). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421007). This variant has been reported to have conflicting or insufficient data to determine the effect on HK1 protein function (PMID: 30778173). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000483739 SCV001762067 likely pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
OMIM RCV000850128 SCV000992292 pathogenic Neurodevelopmental disorder with visual defects and brain anomalies 2019-08-22 no assertion criteria provided literature only

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