Submissions for variant NM_022081.6(HPS4):c.704A>G (p.His235Arg)

gnomAD frequency: 0.00040  dbSNP: rs150166679

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000880339	SCV001023427	benign	not provided	2025-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001146783	SCV001307540	uncertain significance	Hermansky-Pudlak syndrome 4	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702503	SCV005204371	likely benign	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: HPS4 c.704A>G (p.His235Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00064 in 251488 control chromosomes. The observed variant frequency is approximately 1-fold of the estimated maximal expected allele frequency for a pathogenic variant in HPS4 causing Hermansky-Pudlak Syndrome phenotype (0.00052). c.704A>G has been reported in the literature in one individual affected with oculocutaneous albinism (Hutton_2008). 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. The following publication has been ascertained in the context of this evaluation (PMID: 18463683). ClinVar contains an entry for this variant (Variation ID: 708993). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003920509	SCV004744764	likely benign	HPS4-related disorder	2021-04-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).