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]

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Variant: NM_002834.4(PTPN11):c.166A>G (p.Ile56Val)

CA180973

40485 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 43db1167-715a-4f5d-8517-8487caffe8af

HGVS expressions

NM_002834.4:c.166A>G

NM_002834.4(PTPN11):c.166A>G (p.Ile56Val)

NC_000012.12:g.112450346A>G

CM000674.2:g.112450346A>G

NC_000012.11:g.112888150A>G

CM000674.1:g.112888150A>G

NC_000012.10:g.111372533A>G

NG_007459.1:g.36615A>G

NM_002834.3:c.166A>G

NM_080601.1:c.166A>G

NM_001330437.1:c.166A>G

NM_080601.2:c.166A>G

ENST00000351677.6:c.166A>G

ENST00000392597.5:c.166A>G

ENST00000635625.1:n.166A>G

Pathogenic

PS4 PS2 PM2 PP2 PP3

BS2 BS1 BS3 BS4 BP2 BP1 BP4 BP3 BP5 BP7 PM1 PM4 PM5 PS3 PS1 BA1 PM6

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4, PM2, PP3, PP2.

PS4

7 countable cases total. LMM: Variant was identified in 2 separate patients with NS at the LMM. The test was classified as inconclusive and was submitted as a VUS in 2011 GeneDx: Has been identified in 2 probands with minimal clinical info (can't count) PM2, PP3, PP2, and PM1. You could debate adding PP4 for the Atik 2016 article which reported the variant in a patient with suspected Noonan and an affected mother. Either way the variant would still be lpath for us. Labcorp: seen twice in two seemingly un-related test referrals for Noonan syndrome and related disorders It has not been re-evaluated since 2017 as it has not been identified in a subsequent patient specimen. The first case was reported in 2015 in a patient with cardio features but incomplete features of RASopahties. No parental testing was performed and the variant was reported as a VUS-possibly pathogenic. No other pathogenic variants on the remaining genes (BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, SHOC2, SOS1) on the panel were identified. The second case was reported in 2017 in a 1 year old female child with no reported clinical indication. Parental testing was offered but it was not received. No additional testing information is available. No other pathogenic variants on the remaining genes (BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, SHOC2, SOS1) on the panel were identified. Invitae internal data: identified in 2 patients with NS, one was confirmed de novo. The variant has also been identified in a patient with NS (Atik et al. 2016) and a patient with CHD, not counted (Smith et al. 2009)

this study sequenced 32 candidate genes related to CHD's in 190 patients. The variant was identified in a patient with a congenital heart defect. There is no further clinical information for this patient. PubMed:19506109

Variant was identified in patient 7 who is a 9.5 y.o. female with NS: HCM, typical facial appearance, thorax deformity, short stature and mild developmental delay. The variant. The variant was found to segregate in the affected patient's mother PubMed:26817465

PS2

Invitae: 1 confirmed de novo NS patient

PM2

Variant is absent from gnomAD

PP2

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).

PP3

Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3).

BS2