Submissions for variant NM_032383.5(HPS3):c.677A>G (p.His226Arg)

gnomAD frequency: 0.00005  dbSNP: rs188661079

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001150233	SCV001311247	uncertain significance	Hermansky-Pudlak syndrome 3	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.
Invitae	RCV002557234	SCV003524325	uncertain significance	not provided	2022-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 226 of the HPS3 protein (p.His226Arg). This variant is present in population databases (rs188661079, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with HPS3-related conditions. ClinVar contains an entry for this variant (Variation ID: 903115). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001150233	SCV004099415	uncertain significance	Hermansky-Pudlak syndrome 3	2023-10-30	no assertion criteria provided	clinical testing