ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.1846G>A (p.Glu616Lys)

gnomAD frequency: 0.00012  dbSNP: rs775570414
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001106273 SCV001263320 uncertain significance Hermansky-Pudlak syndrome 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV001106273 SCV001653248 likely pathogenic Hermansky-Pudlak syndrome 1 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001828554 SCV002097068 uncertain significance Hermansky-Pudlak syndrome 2021-11-29 criteria provided, single submitter curation The p.Glu616Lys variant in HPS1 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome (Lansdon 2021), and has been identified in 0.02% (6/35438) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP ID: rs775570414). Although this variant has been seen in the general population in a heterozygous state, 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. In summary, the clinical significance of the p.Glu616Lys variant is uncertain. ACMG/AMP Criteria applied: PM3 (Richards 2015).
Invitae RCV002558066 SCV003450624 likely pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 616 of the HPS1 protein (p.Glu616Lys). This variant is present in population databases (rs775570414, gnomAD 0.02%). This missense change has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 34362826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 879090). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HPS1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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