Submissions for variant NM_145331.3(MAP3K7):c.1535C>T (p.Pro512Leu)

dbSNP: rs886039230

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV000254565	SCV001429547	uncertain significance	Frontometaphyseal dysplasia 2	2017-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001530168	SCV001804564	pathogenic	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28498505, 27620904, 27426733, 25899317, 29660408, 29467388)
3billion	RCV000254565	SCV002012036	pathogenic	Frontometaphyseal dysplasia 2	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID: VCV000264698.10, PS1). The variant has been observed in at least four similarly affected unrelated individuals and reported as de novoo (PMID: 27426733, PS2 and PS4) It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.802, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV001530168	SCV003440003	pathogenic	not provided	2022-09-10	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 264698). This variant is also known as p.Pro485Leu. This missense change has been observed in individual(s) with frontometaphyseal dysplasia (PMID: 27426733). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 512 of the MAP3K7 protein (p.Pro512Leu). Experimental studies have shown that this missense change affects MAP3K7 function (PMID: 27426733). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000254565	SCV000320731	pathogenic	Frontometaphyseal dysplasia 2	2016-09-30	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530168	SCV001744913	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001530168	SCV001808914	pathogenic	not provided		no assertion criteria provided	clinical testing