Submissions for variant NM_014168.4(METTL5):c.362A>G (p.Asp121Gly)

gnomAD frequency: 0.00001  dbSNP: rs760916142

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics Laboratory, Gulhane Training and Research Hospital	RCV001263451	SCV001438327	uncertain significance	Intellectual developmental disorder, autosomal recessive 72	2020-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartate with glycine at codon 121 of the METTL5 protein (p.Asp121Gly).The aspartate residue is highly conserved and there is a large physicochemical difference between aspartate and glycine. This variant is present in population databases [rs760916142; 0.000008 (1/120920, ExAC)]. This variant has not been reported in the literature in individuals with METTL5 related disease. In silico analyses are consistent in its predictions as the variant is damaging to the protein structure/function (Mutationtaster:Disease Causing; Provean:Damaging; Revel: Pathogenic; SIFT: Damaging). This variant cosegregate with disease in multiple affected family members. Using ACMG criteria the variant is classified as a “variant of uncertain significance” (PP1, PM2, PP3). 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
Invitae	RCV001880059	SCV002258128	pathogenic	not provided	2023-03-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 983495). This missense change has been observed in individuals with clinical features of METTL5-related intellectual disability syndrome (PMID: 31130284, 36305450). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760916142, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 121 of the METTL5 protein (p.Asp121Gly).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001263451	SCV003035486	likely pathogenic	Intellectual developmental disorder, autosomal recessive 72	2022-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001880059	SCV004147300	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	METTL5: PM2, PM3, PP1:Moderate, PP3