Submissions for variant NM_022081.6(HPS4):c.554G>A (p.Arg185His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002789958	SCV003761112	uncertain significance	Hermansky-Pudlak syndrome 4	2023-01-24	criteria provided, single submitter	curation	The p.Arg185His variant in HPS4 has been reported in 1 individual with Hermansky-Pudlak syndrome 4 (PMID: 31898847, 27176668) and has been identified in 0.08% (24/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs111522254). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg185His variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV003410256	SCV004113245	uncertain significance	HPS4-related disorder	2023-03-14	criteria provided, single submitter	clinical testing	The HPS4 c.554G>A variant is predicted to result in the amino acid substitution p.Arg185His. This variant was reported in heterozygous state in an individual with oculocutaneous albinism, where second variant was not detected (Arcot Sadagopan et al. 2017. PubMed ID: 27176668; Huizing et al. 2020. PubMed ID: 31898847). This variant is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-26866727-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700997	SCV005205371	uncertain significance	not specified	2024-06-03	criteria provided, single submitter	clinical testing	Variant summary: HPS4 c.554G>A (p.Arg185His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 1614152 control chromosomes, predominantly at a frequency of 0.00038 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in HPS4 causing Hermansky-Pudlak Syndrome (3.5e-05 vs 0.00052), allowing no conclusion about variant significance. c.554G>A has been reported in the literature in at least 1 individual affected with Hermansky-Pudlak Syndrome (example, Arcot Sadagopan_2017). This report does 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: 27176668). ClinVar contains an entry for this variant (Variation ID: 2412667). Based on the evidence outlined above, the variant was classified as uncertain significance.