Submissions for variant NM_001987.5(ETV6):c.116G>A (p.Arg39Gln)

gnomAD frequency: 0.00002  dbSNP: rs144209028

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272847	SCV002557253	uncertain significance	Thrombocytopenia 5	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with thrombocytopenia (MIM#616216) (PMID: 25581430, 25807284). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101544	SCV003297697	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 39 of the ETV6 protein (p.Arg39Gln). This variant is present in population databases (rs144209028, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with ETV6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1698990). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago	RCV003151400	SCV003839490	uncertain significance	not specified	2022-08-01	no assertion criteria provided	clinical testing	DNA sequence analysis of the ETV6 gene demonstrated a sequence change, c.116G>A, in exon 2 that results in an amino acid change, p.Arg39Gln. This sequence change does not appear to have been previously described in individuals with ETV6-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.003% (dbSNP rs144209028). The p.Arg39Gln change affects a highly conserved amino acid residue located in a domain of the ETV6 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg39Gln substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg39Gln change remains unknown at this time.