ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.238del (p.Leu80fs)

dbSNP: rs1453977337
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001058686 SCV001223273 pathogenic not provided 2022-12-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 853800). This variant has not been reported in the literature in individuals affected with HPS1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Leu80Cysfs*44) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001827370 SCV002097075 likely pathogenic Hermansky-Pudlak syndrome 2021-12-10 criteria provided, single submitter curation The p.Leu80fs variant in HPS1 has not been previously reported in individuals with Hermansky-Pudlak syndrome but has been identified in 0.0009% (1/113770) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1453977337). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 853800) and has been interpreted as pathogenic by Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 80 and leads to a premature termination codon 44 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

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