Submissions for variant NM_000195.5(HPS1):c.1925del (p.Gly642fs)

dbSNP: rs2136083690

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380350	SCV001578354	pathogenic	not provided	2021-05-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the HPS1 protein. Other variant(s) that result in a similarly extended protein product (p.Tyr645Thrfs*80) have been determined to be pathogenic (PMID: 30387913, 19665357). This suggests that these extensions are likely to be causative of disease. This variant has not been reported in the literature in individuals with HPS1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the HPS1 gene (p.Gly642Glufs*83). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the HPS1 protein and extend the protein by 23 additional amino acid residues.
GeneDx	RCV001380350	SCV001789335	likely pathogenic	not provided	2024-10-31	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 59 amino acids are replaced with 82 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD)
Baylor Genetics	RCV003469647	SCV004199920	likely pathogenic	Hermansky-Pudlak syndrome 1	2023-10-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001380350	SCV005413955	likely pathogenic	not provided	2024-04-03	criteria provided, single submitter	clinical testing	PM2_moderate, PVS1_strong
PreventionGenetics, part of Exact Sciences	RCV004754745	SCV005363046	likely pathogenic	HPS1-related disorder	2024-09-17	no assertion criteria provided	clinical testing	The HPS1 c.1925delG variant is predicted to result in a frameshift and premature protein termination (p.Gly642Glufs*83). XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX which is predicted to result in a frameshift and extension of the normal open reading frame (p.Gly642Glufs*83) (the canonical stop codon is at position p.701). To our knowledge, this variant has not been reported in the literature. However, this variant is similar in form and gene position to other reported variants (c.1887delC,p.Val630Serfs*95; c.1932delC,p.Tyr645Thrfs*80) in individuals with Oculocutaneous albinism or Hermansky‐Pudlak syndrome (Wei et al. 2011. PubMed ID: 21458243; Wei et al. 2018. PubMed ID: 30387913). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1068714/). Taken together, this variant is interpreted as likely pathogenic.