ClinVar Miner

Submissions for variant NM_032383.5(HPS3):c.1163+1G>A (rs201227603)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724652 SCV000331832 pathogenic not provided 2016-02-16 criteria provided, single submitter clinical testing
GeneReviews RCV000004872 SCV000041519 pathologic Hermansky-Pudlak syndrome 3 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000724652 SCV000936866 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the HPS3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs201227603, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another HPS3 variant in several individuals of Ashkenazi Jewish origin, affected with Hermansky-Pudlak syndrome (HPS) (PMID: 11590544). This variant is also known as 1303+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 4609). Experimental studies have shown that this change affects RNA splicing, causing skipping of exon 5 (PMID: 11590544). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HPS3 are known to be pathogenic (PMID: 11590544). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826142 SCV000967672 pathogenic Hermansky-Pudlak syndrome 2018-11-08 criteria provided, single submitter clinical testing The c.1163+1G>A variant, also known as c.1303+1G>A, in HPS3 has been reported in the homozygous state in 3 individuals with Hermansky Pudlak syndrome type 3 and in the compound heterozygous state with other splice site variants in 2 individ uals with Hermansky Pudlak syndrome type 3, all of whom had Ashkenazi Jewish anc estry (Huizing 2001). It has also been identified in 0.17% (17/10150) of Ashkena zi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence. Stud ies have demonstrated that this variant cases skipping of exon 5, resulting in a premature translational stop at codon 350, which is predicted to produce a trun cated or absent protein (Huizing 2001). Loss of function of the HPS3 gene is an established disease mechanism in Hermansky Pudlak syndrome type 3, which is a mi lder form of Hermansky Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky Pudlak syndrome . ACMG/AMP Criteria applied: PVS1, PM3_Strong, PS3_Supporting.
OMIM RCV000004872 SCV000025048 pathogenic Hermansky-Pudlak syndrome 3 2001-11-01 no assertion criteria provided literature only

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