Variant: NM_030662.3(MAP2K2):c.692G>A (p.Arg231His)

CA9090854

543999 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 9f74ed62-a0c3-40e1-b0b2-7aa680c29fe2

Approved on: 2019-05-17

Published on: 2019-06-28

HGVS expressions

NM_030662.3:c.692G>A
NM_030662.3(MAP2K2):c.692G>A (p.Arg231His)
NC_000019.10:g.4101032C>T
CM000681.2:g.4101032C>T
NC_000019.9:g.4101030C>T
CM000681.1:g.4101030C>T
NC_000019.8:g.4052030C>T
NG_007996.1:g.28097G>A
ENST00000262948.9:c.692G>A
ENST00000394867.8:c.401G>A
ENST00000593364.5:n.639G>A
ENST00000597008.5:n.293G>A
ENST00000597263.5:n.156G>A
ENST00000599021.1:n.16G>A
ENST00000601786.5:n.993G>A
ENST00000602167.5:n.412G>A

Uncertain Significance

• Met criteria codes: PP2 PP3

• Not Met criteria codes: BS2 BS1 BS4 BS3 PS1 PS2 PS3 PS4 BP4 BP3 BP1 BP2 BP5 BP7 BA1 PP1 PM1 PM5 PM4 PM6 PM2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.692G>A (p.Arg231His) variant in MAP2K2 has been identified in a patient with clinical features consistent with cardiomyopathy (PS4 not met; Invitae internal data, GTR Lab ID 500031; ClinVar SCV000776886.1). 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.Arg231His variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg231His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): 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.Arg231His variant may impact the protein (PP3).

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: Variant's frequency in Other alleles is just under BS1 cutoff but only 1 allele so shouldn't be applied.
• BS4: 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
• 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
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Invitae: Observed variant in a patient with cardiomyopathy
• BP4: 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
• BP1: 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
• 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
• BA1: 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
• PM1: aa 47-65, 128-138
• PM5: p.Arg231Leu variant has also been identiifed, but will not be classified as Pathogenic
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: This variant has been identified in 1/4152 Other alleles in gnomAD. therefore PM2 cannot be applied.