ClinVar Miner

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

dbSNP: rs1554892764
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Total submissions: 6
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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).

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