Submissions for variant NM_022552.5(DNMT3A):c.2311C>T (p.Arg771Ter)

gnomAD frequency: 0.00004  dbSNP: rs779626155

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486209	SCV000567401	pathogenic	not provided	2015-08-13	criteria provided, single submitter	clinical testing	The R771X variant in the DNMT3A gene has not been reported previously as congenital pathogenic variant.However, it has been reported as a somatic variant in an individual with aplastic anemia (Kulasekararajet al., 2014). This variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. The R771X variant was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. We interpret R771X as a pathogenic variant.
Invitae	RCV001237885	SCV001410668	pathogenic	Tatton-Brown-Rahman overgrowth syndrome	2023-06-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419534). This variant has not been reported in the literature in individuals affected with DNMT3A-related conditions. This variant is present in population databases (rs779626155, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg771*) in the DNMT3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNMT3A are known to be pathogenic (PMID: 24614070).
CeGaT Center for Human Genetics Tuebingen	RCV000486209	SCV001746597	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338604	SCV004047018	pathogenic	Acute myeloid leukemia		criteria provided, single submitter	clinical testing	The stop gain c.2311C>T (p.Arg771Ter) variant has been reported previously as a somatic variant in an individual affected with myelodysplastic syndrome and refractory anemia (Zhao X. et al., 2017). Germline DNMT3A mutation in familial acute myeloid leukemia has been previously reported (DiNardo CD. et al., 2021). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.