ClinVar Miner

Submissions for variant NM_022081.6(HPS4):c.557C>T (p.Ser186Leu)

gnomAD frequency: 0.00112  dbSNP: rs61729175
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000370644 SCV000332057 uncertain significance not provided 2015-06-15 criteria provided, single submitter clinical testing
Invitae RCV000370644 SCV001120285 likely benign not provided 2024-01-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479088 SCV004222820 likely benign not specified 2023-11-02 criteria provided, single submitter clinical testing Variant summary: HPS4 c.557C>T (p.Ser186Leu) 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. The variant allele was found at a frequency of 0.00026 in 251390 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in HPS4 causing Hermansky-Pudlak Syndrome phenotype (0.00052), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.557C>T in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences RCV003909909 SCV004718559 likely benign HPS4-related condition 2023-11-29 criteria provided, single submitter 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).

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