ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.695C>T (p.Ala232Val)

gnomAD frequency: 0.00006  dbSNP: rs764420988
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000309402 SCV000359665 uncertain significance Hermansky-Pudlak syndrome 1 2018-01-12 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.
Broad Institute Rare Disease Group, Broad Institute RCV001828293 SCV002097062 uncertain significance Hermansky-Pudlak syndrome 2021-11-29 criteria provided, single submitter curation The p.Ala232Val variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 26785811) and has been identified in 0.03% (4/8856) of Ashkenazi Jewish chromosomes (including one homozygous occurrence) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764420988). 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. This variant has also been reported in ClinVar (Variation ID#: 298345) and has been interpreted as VUS by Illumina Clinical Services Laboratory (Illumina). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala232Val variant is uncertain. ACMG/AMP Criteria applied: BP4, PM3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844115 SCV002103400 uncertain significance not specified 2022-02-23 criteria provided, single submitter clinical testing Variant summary: HPS1 c.695C>T (p.Ala232Val) results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, second Longin domain (IPR043971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 160342 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in HPS1 causing Hermansky-Pudlak Syndrome (8.1e-05 vs 0.00096), allowing no conclusion about variant significance. c.695C>T has been reported in the literature in a homozygous individual affected with oculocutaneous albinism (Khan_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000309402 SCV002782567 uncertain significance Hermansky-Pudlak syndrome 1 2022-04-25 criteria provided, single submitter clinical testing
Invitae RCV002520518 SCV003522602 uncertain significance not provided 2022-10-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 232 of the HPS1 protein (p.Ala232Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 26785811). ClinVar contains an entry for this variant (Variation ID: 298345). 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 not expected to disrupt HPS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Preventiongenetics, part of Exact Sciences RCV003401283 SCV004104062 uncertain significance HPS1-related condition 2023-05-31 criteria provided, single submitter clinical testing The HPS1 c.695C>T variant is predicted to result in the amino acid substitution p.Ala232Val. This variant was reported in homozygous state in an individual with albinism (Khan et al 2016. PubMed ID: 26785811). This variant is reported in 0.034% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-100190401-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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