Submissions for variant NM_000195.5(HPS1):c.787C>T (p.Arg263Trp)

gnomAD frequency: 0.00065  dbSNP: rs145042327

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000974466	SCV001122289	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001103326	SCV001260069	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	RCV000974466	SCV001817307	uncertain significance	not provided	2021-04-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV001103326	SCV003808765	uncertain significance	Hermansky-Pudlak syndrome 1	2021-12-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526790	SCV005040635	likely benign	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: HPS1 c.787C>T (p.Arg263Trp) results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, second Longin domain (IPR043971) 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 0.00069 in 248994 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.14 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.787C>T has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hermansky-Pudlak Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 791493). Based on the evidence outlined above, the variant was classified as likely benign.