Evidence Repository - Clinical Genome Resources

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

Variant: NM_002834.4(PTPN11):c.167T>C (p.Ile56Thr)

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CA243707917

477669 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2a9a7233-77c0-4d04-a2e1-0a1ac478a404

Approved on: 2019-05-10

Published on: 2019-06-28

HGVS expressions

NM_002834.4:c.167T>C

NM_002834.4(PTPN11):c.167T>C (p.Ile56Thr)

NC_000012.12:g.112450347T>C

CM000674.2:g.112450347T>C

NC_000012.11:g.112888151T>C

CM000674.1:g.112888151T>C

NC_000012.10:g.111372534T>C

NG_007459.1:g.36616T>C

NM_002834.3:c.167T>C

NM_080601.1:c.167T>C

NM_001330437.1:c.167T>C

NM_080601.2:c.167T>C

ENST00000351677.6:c.167T>C

ENST00000392597.5:c.167T>C

ENST00000635625.1:n.167T>C

Likely Pathogenic

PP2 PP3 PM5 PM2 PS4_Supporting

PS1 PS2 PS3 BP1 BP4 BP2 BP3 BP7 BP5 BA1 PP1 PM4 PM1 PM6 BS2 BS1 BS4 BS3

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.167T>C (p.Ile56Thr) variant in PTPN11 has been identified in 2 related patients with clinical features of a RASopathy (PS4_Supporting, PP1; Invitae internal data; GTR Lab ID 500031; ClinVar SCV000659038.1). A different pathogenic missense variant (p.Ile56Val) has been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40485). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the PTPN11 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.Ile56Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PP1, PM2, PM5, PP2, PP3.

PP2

Variant is in PTPN11

PP3

Variant has a REVEL score of 0.969

PM5

Variant is at the same AA codon as the p.Ile56Val variant which has been classified as Pathogenic

PM2

Variant is absent from gnomAD.

PS4_Supporting

Invitae: observed variant in two siblings who had features of NS. Tested unaffected mother and unaffected sister and they were both negative, but that was the extend of additional testing they were able to do.

PS1