ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.1888G>A (p.Val630Ile)

gnomAD frequency: 0.00144  dbSNP: rs139061260
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000910982 SCV001056035 likely benign not provided 2024-01-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000020190 SCV001262072 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.
GeneDx RCV000910982 SCV001994196 uncertain significance not provided 2019-07-18 criteria provided, single submitter clinical testing Reported in published literature in an individual with pulmonary fibrosis; however, additional clinical information and familial segregation was not provided (Stearman et al., 2019); Reported as a benign variant in published literature, however, supporting details regarding how this classification was determined were not provided (Shotelersuk et al., 1998; Huizing et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12125811, 30985222, 9787100, 11208073)
Genetic Services Laboratory, University of Chicago RCV001818168 SCV002066373 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818168 SCV003922565 likely benign not specified 2023-03-23 criteria provided, single submitter clinical testing Variant summary: HPS1 c.1888G>A (p.Val630Ile) results in a conservative amino acid change located in the FUZ/MON1/HPS1, third Longin domain (IPR043970) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 248998 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HPS1 causing Hermansky-Pudlak Syndrome phenotype (0.00096), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1888G>A has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome however in the presence of Pro324 frameshift indicating a benign role for this variant (Oh_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cassified the variant as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences RCV003914856 SCV004733180 likely benign HPS1-related disorder 2023-07-07 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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