Submissions for variant NM_000195.5(HPS1):c.678_680delinsTGT (p.Ser227Val)

dbSNP: rs1554892764

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592693	SCV000703401	likely benign	not specified	2016-11-04	criteria provided, single submitter	clinical testing
Invitae	RCV000941281	SCV001087164	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002497255	SCV002808446	likely benign	Hermansky-Pudlak syndrome 1	2022-04-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000941281	SCV003803231	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000592693	SCV004099520	likely benign	not specified	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: HPS1 c.678_680delinsTGT (p.Ser227Val) is part of a multinucleotide combination of 10-100190416-C-A (c.680G>T and p.Ser227Ile); 100190417-T-C (c.679A>G and p.Ser227Gly) and 10-100190418-G-A (c.678C>T and p.Ala226Ala) that results in a non-conservative amino acid change located in the FUZ/MON1/HPS1, second Longin domain (IPR043971) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 150866 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database (v3.1, reported as the aforementioned 3 SNVs with identical allele counts and reported to occur in the same phase), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.2-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 African or African-American origin. To our knowledge, no occurrence of c.678_680delinsTGT in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003952955	SCV004770825	likely benign	HPS1-related disorder	2021-01-04	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).