Submissions for variant NM_022081.6(HPS4):c.1132C>T (p.Gln378Ter)

dbSNP: rs369053765

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214159	SCV000271230	likely pathogenic	Hermansky-Pudlak syndrome	2015-03-11	criteria provided, single submitter	clinical testing	The p.Gln378X variant in HPS4 has not been previously reported in individuals wi th Hermansky-Pudlak syndrome (HPS), but has been identified in 3/66728 European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org/ ; dbSNP rs369053765). This nonsense variant leads to a premature termination cod on at position 378, which is predicted to lead to a truncated or absent protein. Complete loss of HPS4 function has been reported in several individuals with HP S. In summary, although additional studies are required to fully establish its c linical significance, the p.Gln378X variant is likely pathogenic.
Invitae	RCV001853424	SCV002195796	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln378*) in the HPS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS4 are known to be pathogenic (PMID: 12664304). This variant is present in population databases (rs369053765, ExAC 0.004%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 31898847). ClinVar contains an entry for this variant (Variation ID: 228266). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002517523	SCV003761107	likely pathogenic	Hermansky-Pudlak syndrome 4	2023-01-24	criteria provided, single submitter	curation	The p.Gln378Ter variant in HPS4 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome 4 (PMID: 31898847) and has been identified in 0.004% (4/113758) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs369053765). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 228266) and has been interpreted as pathogenic or likely pathogenic by Invitae and Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine). This nonsense variant leads to a premature termination codon at position 378, which is predicted to lead to a truncated or absent protein. Loss of function of the HPS4 gene is strongly associated to autosomal recessive Hermansky-Pudlak syndrome 4. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Hermansky-Pudlak syndrome 4. ACMG/AMP Criteria applied: PVS1_strong, PM3_supporting, PM2_supporting (Richards 2015).
Baylor Genetics	RCV002517523	SCV004192343	pathogenic	Hermansky-Pudlak syndrome 4	2023-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000214159	SCV004241500	pathogenic	Hermansky-Pudlak syndrome	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: HPS4 c.1132C>T (p.Gln378X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes. c.1132C>T has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Huizing_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31898847). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.