Submissions for variant NM_000195.5(HPS1):c.398+5G>A

dbSNP: rs281865077

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851672	SCV002238952	pathogenic	not provided	2024-11-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the HPS1 gene. It does not directly change the encoded amino acid sequence of the HPS1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 9497254, 24583434, 30634918). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5283). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001851672	SCV002599677	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32487952, 25525159, 27284308, 30634918, 32725903, 33365035, 20301464, 10971344, 27176668, Kageshima2021[paper], 9497254, 19398212, 33023548, 15519141, 24583434, 27593200)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387717	SCV004100293	pathogenic	Hermansky-Pudlak syndrome	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: HPS1 c.398+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example: Suzuki_2004). The variant was absent in 250990 control chromosomes (gnomAD). c.398+5G>A has been reported in the literature in multiple individuals affected with Hermansky-Pudlak Syndrome (example: Ito_2005). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16185271, 15519141). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000005601	SCV004199924	pathogenic	Hermansky-Pudlak syndrome 1	2024-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001851672	SCV004704314	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	HPS1: PM3:Very Strong, PM2, PS3:Supporting
OMIM	RCV000005601	SCV000025783	pathogenic	Hermansky-Pudlak syndrome 1	2000-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000005601	SCV000040531	not provided	Hermansky-Pudlak syndrome 1		no assertion provided	literature only