Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_030662.3(MAP2K2):c.692G>T (p.Arg231Leu)

CA296133

40818 (ClinVar)

Gene: MAP2K2
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: c77c7f8b-de11-4d2a-b1e3-d7190a41ba9f
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

NM_030662.3:c.692G>T
NM_030662.3(MAP2K2):c.692G>T (p.Arg231Leu)
NC_000019.10:g.4101032C>A
CM000681.2:g.4101032C>A
NC_000019.9:g.4101030C>A
CM000681.1:g.4101030C>A
NC_000019.8:g.4052030C>A
NG_007996.1:g.28097G>T
ENST00000262948.9:c.692G>T
ENST00000394867.8:c.401G>T
ENST00000593364.5:n.639G>T
ENST00000597008.5:n.293G>T
ENST00000597263.5:n.156G>T
ENST00000599021.1:n.16G>T
ENST00000601786.5:n.993G>T
ENST00000602167.5:n.412G>T
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Uncertain Significance

Met criteria codes 4
PP2 PP3 PM2 PS4_Supporting
Not Met criteria codes 19
PS3 PS1 PS2 PP1 PM6 PM1 PM4 PM5 BA1 BS2 BS1 BS3 BS4 BP1 BP4 BP2 BP3 BP5 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3.
Met criteria codes
PP2
The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581).
PP3
Computational prediction tools and conservation analysis suggest that the p.Arg231Leu variant may impact the protein (PP3).
PM2
This variant is absent in gnomAD.
PS4_Supporting
This variant was observed in 2 patients at GeneDx (one without clinical information and one with clincial diagnosis of NSML) Invitae: observed MAP2K2 p.Arg231Leu once, in patient with features of NSML. It was absent from ExAC/gnomAD and the predictors were all deleterious. We have not tested any additional family members. These two NSML occurrences make the variant meet PS4_Supporting, despite MAP2K2 not having a lot of information to associate it with NSML
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
Neither report seems to indicate that these occurrences were de novo
PM1
aa 47-65, 128-138 are the regions defined by the RAS VCEP for MAP2K2
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Variant at same codon as the NM_030662.3(MAP2K2):c.692G>A (p.Arg231His) variant in ClinVar which will also need to be assessed.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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