Submissions for variant NM_004667.6(HERC2):c.10474T>C (p.Ser3492Pro)

gnomAD frequency: 0.00021  dbSNP: rs185865505

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520105	SCV000621698	uncertain significance	not provided	2025-03-06	criteria provided, single submitter	clinical testing	Has not been published as a clinical report in a peer reviewed journal as a pathogenic variant, nor as a benign variant, to our knowledge; However, p.(S3492P) has been reported in an abstract by Hong et al., 2016 and subsequently cited in a review article, in an individual with intention tremors, Henoch-Schonlein purpura, recurrent sinopulmonary infections, and lymphoma who also harbored an additional HERC2 variant on the opposite allele but it is unknown if this individual harbored variants in other genes that my have potentially contributed to the phenotype (Hong, C. et al. 2016, 22nd Annual ISCT Meeting, Cytotherapy, Volume 18, Issue 6, S3; PMID: 34370298); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34370298)
Ambry Genetics	RCV002525247	SCV003553690	likely benign	Inborn genetic diseases	2022-05-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003935390	SCV004747683	benign	HERC2-related disorder	2024-09-11	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ophthalmology Lab, The First People's Hospital of Yunnan Provience	RCV004730975	SCV005326283	likely pathogenic	concomitant exotropia	2024-08-30	no assertion criteria provided	clinical testing	Dominant inheritance. Diseases associated with HERC2 include intellectual developmental disorder, autosomal recessive and skin/hair/eye pigmentation.