Variant classification summary

NM_002755.3:c.146G>A

MAP2K1 · NP_002746.1:p.(Arg49His) · NM_002755.3

GRCh37: chr15:66727430 G>A · GRCh38: chr15:66435092 G>A

Gene: MAP2K1 Transcript: NM_002755.3

Final call

VUS

PS2 moderate PM1 moderate PP3 supporting

Variant details

Gene

MAP2K1

Transcript

NM_002755.3

Protein

NP_002746.1:p.(Arg49His)

gnomAD AF

3.097701505482932e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002755.3:c.146G>A (p.Arg49His) in MAP2K1 is a missense variant located within the VCEP-designated critical functional domain spanning amino acids 43-61, satisfying PM1 at Moderate strength.

2

A confirmed de novo occurrence of this variant was reported in a patient with cardio-facio-cutaneous syndrome, with both maternity and paternity confirmed, satisfying PS2 at Moderate strength (1 point under VCEP scoring).

3

The REVEL in silico score is 0.707, meeting the VCEP PP3 threshold of ≥0.7 for missense variants at Supporting strength.

4

This variant is present at extremely low frequency in gnomAD (AF ~0.0004%), far below both the BA1 (≥0.05%) and BS1 (≥0.025%) thresholds, and present in only 1 allele in v2.1 and 5 alleles in v4.1.

5

No alternative pathogenic missense change at codon 49 was identified (PM5 not met), and the variant is not absent from gnomAD controls (PM2 not met per VCEP requirement for complete absence).

6

PP2 (missense constraint z-score) remains unassessed pending gnomAD constraint data retrieval. If the MAP2K1 missense z-score exceeds 3.09, PP2_Supporting would also be met.

7

ClinVar lists this variant as Uncertain significance (1 submitter, SCV003504233, Labcorp Genetics). No expert panel classification is available.

8

Under the RASopathy VCEP v2.3.0 combination rules, the current met criteria (PM1_Moderate + PS2_Moderate + PP3_Supporting) do not satisfy any rule for Likely Pathogenic or Pathogenic classification. If PP2_Supporting is also met, Rule14 (2 Moderate + ≥2 Supporting) would be satisfied, yielding Likely Pathogenic.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable per the ClinGen RASopathy VCEP v2.3.0. This is a missense variant (c.146G>A, p.Arg49His), not a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon deletion).	cspec
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Arg49His) from a different nucleotide change has been identified in ClinVar or the literature for MAP2K1 or the analogous MAP2K2 residue.	cspec clinvar
PS2	Met	A confirmed de novo occurrence of NM_002755.3:c.146G>A (p.Arg49His) was reported in a patient with cardio-facio-cutaneous syndrome; both parents were tested and the variant was absent in both, satisfying 1 point under the RASopathy VCEP PS2 point-based scoring system (Moderate strength).	cspec
PS3	Not met	No evidence that p.Arg49His has been evaluated in VCEP-approved functional assays with a demonstrated damaging effect. The variant is not listed among validated pathogenic controls in the RASopathy VCEP Approved Functional Studies spreadsheet. OncoKB annotates the variant as Likely Neutral, which is inconsistent with a damaging functional effect.	cspec oncokb vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:32641410
PS4	Not met	Insufficient case-control evidence to apply PS4 under the VCEP point-based system. The variant is reported in ClinVar as Uncertain significance by a single clinical laboratory (SCV003504233, Labcorp Genetics). No curated case-control study demonstrating statistically significant enrichment of this variant in RASopathy patients versus controls is available.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not defined in the ClinGen RASopathy VCEP v2.3.0 criteria specifications. This criterion (reputable source reports variant as pathogenic without available evidence) is not for use under this VCEP framework, consistent with the VCEP's treatment of PP5 and BP6.	cspec
PM1	Met	The variant affects amino acid position 49 (p.Arg49His), which lies within the VCEP-designated critical functional domain spanning amino acids 43-61 of MAP2K1. This region is specified in the RASopathy VCEP supplementary table as a well-established functional domain eligible for PM1 at Moderate strength.	cspec
PM2	Not met	The RASopathy VCEP PM2 rule requires the variant to be absent from gnomAD controls. NM_002755.3:c.146G>A is present in gnomAD v2.1 at an allele frequency of 3.98e-6 (1/251,360 alleles) and in gnomAD v4.1 at 3.10e-6 (5/1,614,100 alleles). Because the variant is observed in population controls, PM2_Supporting cannot be applied.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No alternative pathogenic or likely pathogenic missense variant at codon 49 of MAP2K1 (or the analogous MAP2K2 residue) was identified. The VCEP PM5 rule requires at least one [likely] pathogenic residue change at the same codon for Moderate strength; no such comparator variant was found in ClinVar or the literature.	cspec clinvar pm5_candidates
PM6	Not met	The single de novo observation of c.146G>A (PMID:16439621) had both maternity and paternity confirmed, qualifying it as PS2 rather than PM6. No separate de novo events lacking full parental confirmation were identified for this variant. Under the SVI point-based system, a given de novo event is scored under either PS2 or PM6, not both.	cspec
PP1	Not met	No evidence of co-segregation of c.146G>A in multiple affected family members was identified. Cardio-facio-cutaneous syndrome is typically caused by de novo mutations, and familial cases with this variant have not been reported.
PP2	Not assessed	The RASopathy VCEP PP2 rule requires a missense z-score >3.09 in gnomAD for MAP2K1. The gnomAD missense constraint metric (z-score) was not retrieved during evidence collection and could not be verified.	cspec
PP3	Met	The REVEL score for NM_002755.3:c.146G>A (p.Arg49His) is 0.707, which meets the RASopathy VCEP PP3 threshold of REVEL ≥ 0.7 for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico evidence derives entirely from the REVEL missense prediction.	cspec revel spliceai
PP4	N/A	PP4 is not applicable per the ClinGen RASopathy VCEP v2.3.0. The VCEP directs users to PS4 for phenotype-based evidence instead.	cspec
PP5	N/A	PP5 is not for use under the ClinGen RASopathy VCEP v2.3.0, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The RASopathy VCEP BA1 threshold is a gnomAD filtering allele frequency ≥ 0.05%. This variant has an allele frequency of approximately 0.0004% (3.98e-6 in v2.1, 3.10e-6 in v4.1), far below the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The RASopathy VCEP BS1 threshold is a gnomAD filtering allele frequency ≥ 0.025%. This variant has an allele frequency of approximately 0.0004%, far below the BS1 threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No evidence that NM_002755.3:c.146G>A has been observed in a healthy adult individual without a RASopathy phenotype. The single allele observed in gnomAD v2.1 (Admixed American population) lacks phenotypic annotation and cannot be confirmed as a healthy carrier.	gnomad_v2 cspec
BS3	N/A	BS3 is not applicable per the ClinGen RASopathy VCEP v2.3.0. The VCEP does not define strength rules for BS3 in this framework, consistent with the panel's assessment that well-established functional studies showing no damaging effect are not sufficient for benign classification in RASopathy genes.	cspec
BS4	Not met	No evidence of non-segregation of c.146G>A in affected family members has been reported. Given that CFC syndrome is typically caused by de novo mutations, non-segregation data is not expected but its absence precludes application of BS4.
BP1	N/A	BP1 under the RASopathy VCEP applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, or multi-exon deletion) in genes where loss of function is not an established disease mechanism. NM_002755.3:c.146G>A is a missense variant (p.Arg49His), not a truncating variant.	cspec
BP2	Not met	No evidence that c.146G>A has been observed in trans with another pathogenic MAP2K1 variant or that an alternative molecular cause in MAP2K1 explains the phenotype in a patient carrying this variant. No evidence satisfying the VCEP BP2 point-based scoring system was identified.	cspec
BP4	Not met	The RASopathy VCEP BP4 threshold for missense variants is REVEL ≤ 0.3. The REVEL score for p.Arg49His is 0.707, which exceeds the BP4 threshold and instead meets PP3 (REVEL ≥ 0.7).	cspec revel
BP5	Not met	No evidence of an alternative molecular cause in a different gene that fully explains the RASopathy phenotype in a patient carrying c.146G>A. No evidence satisfying the VCEP BP5 point-based scoring criteria was identified.	cspec
BP6	N/A	BP6 is not for use under the ClinGen RASopathy VCEP v2.3.0, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_002755.3:c.146G>A is a missense variant (p.Arg49His), not a synonymous variant.	cspec

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