Submissions for variant NM_022552.5(DNMT3A):c.911_913del (p.Ser304del)

dbSNP: rs1674984864

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001171613	SCV001334411	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266051	SCV001444223	likely pathogenic	Inborn genetic diseases	2024-09-04	criteria provided, single submitter	clinical testing	The c.911_913delCCT (p.S304del) alteration is located in exon 8 (coding exon 7) of the DNMT3A gene. This alteration consists of an in-frame deletion of 3 nucleotides from nucleotide position c.911 to c.913, resulting in the deletion of a serine at amino acid position 304. for Heyn-Sproul-Jackson syndrome; however, its clinical significance for Tatton-Brown-Rahman syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with Heyn-Sproul-Jackson syndrome; in at least one individual, this variant has been determined to be the result of a de novo mutation (Wang, 2023; external communications). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV002510586	SCV002820271	uncertain significance	Heyn-Sproul-Jackson syndrome		criteria provided, single submitter	clinical testing	The in-frame deletion p.S304del in DNMT3A (NM_175629.2) has been previously submitted to ClinVar with conflicting interpretations of pathogenicity (Uncertain Significance/Likely Pathogenic). It has not been reported in literature and hence independent assesment of submitted classification is not possible. The p.S304del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a serine at position 304 of the DNMT3A gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The p.S304del variant is not in a repeat region. The p.S304del variant results in a deletion of 3 bases that are predicted conserved by GERP++ and PhyloP. The nucleotide c.911 in DNMT3A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002558718	SCV003012091	uncertain significance	Tatton-Brown-Rahman overgrowth syndrome	2022-09-26	criteria provided, single submitter	clinical testing	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. This variant, c.911_913del, results in the deletion of 1 amino acid(s) of the DNMT3A protein (p.Ser304del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNMT3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 916110). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown.
3billion, Medical Genetics	RCV002510586	SCV003841423	uncertain significance	Heyn-Sproul-Jackson syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been reported as pathogenic and VUS for DNMT3A -related disorder (ClinVar ID: VCV000916110). The evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.