Submissions for variant NM_001987.5(ETV6):c.1195C>T (p.Arg399Cys)

dbSNP: rs724159945

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001824288	SCV002073991	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Observed in individuals with a personal history consistent with pathogenic variants in this gene, with segregation in affected individuals from a single family in the literature (Moriyama 2015, Zhang 2015); Published functional studies demonstrate a damaging effect: dominant negative variant leading to mislocalization of protein in cytoplasm and reduced repression of necessary genes for hematopoietic differentiation (Topka 2015, Zhang 2015); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26522332, 26219557, 28637624, 25581430, 26102509, 28555414)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000157609	SCV002569283	pathogenic	Thrombocytopenia 5		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157609	SCV003800900	pathogenic	Thrombocytopenia 5	2023-01-24	criteria provided, single submitter	clinical testing	Variant summary: ETV6 c.1195C>T (p.Arg399Cys) results in a non-conservative amino acid change located in the Ets domain (IPR000418) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes (gnomAD). c.1195C>T has been reported in the literature in individuals affected with Thrombocytopenia and malignancy, and the variant segregated with the disease (examples: Nishi_2021 and Zhang_2015). Published functional studies demonstrate a damaging effect of the variant on protein function. Zhang_2015 demonstrated p.Arg399Cys abrogate DNA binding by ETV6 and failed to repress firefly luciferase reporter constructs containing the MMP3 or PF4 promoter. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001824288	SCV004295844	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the ETV6 protein (p.Arg399Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ETV6-related conditions (PMID: 25581430, 26522332). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162220). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ETV6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 26102509, 32693409). This variant disrupts the p.Arg399 amino acid residue in ETV6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25581430, 32693409). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center	RCV000149802	SCV000195553	pathogenic	Hematologic neoplasm; Thrombocytopenia	2014-11-30	no assertion criteria provided	research
OMIM	RCV000157609	SCV000207418	pathogenic	Thrombocytopenia 5	2015-02-01	no assertion criteria provided	literature only