Submissions for variant NM_001987.5(ETV6):c.641C>T (p.Pro214Leu)

dbSNP: rs724159947

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001818340	SCV002065858	pathogenic	not provided	2021-08-12	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ETV6 gene demonstrated a sequence change, c.641C>T, in exon 5 that results in an amino acid change, p.Pro214Leu. This pathogenic sequence change has previously been described in multiple individuals with ETV6-related thrombocytopenia and has been shown to segregate with disease in at least two families (PMID: 25581430, 25807284, 27663637, 31704777, 32367453). Additionally, experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284, 32367453). This sequence change has not been described in population databases including gnomAD (dbSNP rs724159947). The p.Pro214Leu change affects a highly conserved amino acid residue located in a domain of the ETV6 protein that is known to be functional. The p.Pro214Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggest that, the c.641C>T change is pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000157611	SCV002573466	likely pathogenic	Thrombocytopenia 5		criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000157611	SCV002764686	pathogenic	Thrombocytopenia 5	2020-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001818340	SCV003440969	pathogenic	not provided	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 214 of the ETV6 protein (p.Pro214Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial thrombocytopenia with leukemia (PMID: 25581430, 25807284, 31704777, 33768492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162222). 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 not expected to disrupt ETV6 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ETV6 function (PMID: 25581430, 25807284). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000157611	SCV004175267	likely pathogenic	Thrombocytopenia 5	2023-06-20	criteria provided, single submitter	clinical testing	The ETV6 c.641C>T variant is classified as Likely Pathogenic (PS3_Supporting, PS4_Moderate, PM2, PP1_Moderate) The ETV6 c.641C>T variant is a single nucleotide change in exon 5/8 of the ETV6 gene, which is predicted to change the amino acid proline at position 214 in the protein to leucine. Experimental studies have demonstrated that this sequence change impacts the function of the ETV6 protein (PMID: 25581430, 25807284). The p.Pro214Leu variant affects a highly conserved amino acid residue located in a linker inhibitory domain (amino acids 127–331) that indirectly promotes DNA binding (PS3_Supporting). The variant has been reported in multiple unrelated proband(s) with a clinical presentation of Thrombocytopenia. In addition, this variant has been reported in a patient subsequently developing a T cell/myloid mixed phenotype acute leukemia (MPAL) (PMID:25581430) (PS4_Moderate).This variant is absent from population databases (PM2). This variant co-segregates with disease demonstrated in PMID:27666367 which noted four generations of affected family members. (PP1_moderate). The variant has been reported in dbSNP (rs724159947) and in the HGMD database: CM150819. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162222).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000157611	SCV005689427	pathogenic	Thrombocytopenia 5	2025-02-05	criteria provided, single submitter	clinical testing	The ETV6 c.641C>T (p.Pro214Leu) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function. Functional studies have shown that this variant results in a loss of transcriptional repressor activity, as evidenced by luciferase reporter assays, and disrupts normal nuclear localization of the ETV6 protein inhibiting the wild-type ETV6-mediated repression through a dominant-negative mechanism (PMID: 25581430, 25807284). This variant has been reported in multiple individuals with thrombocytopenia, including three who developed B-ALL, and It was observed to segregate at least two families. (PMID: 25581430, 25807284, 31704777, 33768492). In summary, this variant meets criteria to be classified as pathogenic.
Akiko Shimamura Lab, Fred Hutchinson Cancer Research Center	RCV000149804	SCV000195555	likely pathogenic	Hematologic neoplasm; Thrombocytopenia	2014-11-30	no assertion criteria provided	research
OMIM	RCV000157611	SCV000207420	pathogenic	Thrombocytopenia 5	2015-05-01	no assertion criteria provided	literature only
GeneReviews	RCV001281572	SCV001468882	not provided	Acute myeloid leukemia		no assertion provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000157611	SCV002029215	pathogenic	Thrombocytopenia 5	2021-10-14	no assertion criteria provided	clinical testing