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_002834.4(PTPN11):c.215C>T (p.Ala72Val)

CA215451

41443 (ClinVar)

Gene: PTPN11
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4ec5038d-8e1d-4c2b-8b78-b4203d3b5c2d
Approved on: 2020-03-25
Published on: 2020-03-25

HGVS expressions

NM_002834.4:c.215C>T
NM_002834.4(PTPN11):c.215C>T (p.Ala72Val)
NC_000012.12:g.112450395C>T
CM000674.2:g.112450395C>T
NC_000012.11:g.112888199C>T
CM000674.1:g.112888199C>T
NC_000012.10:g.111372582C>T
NG_007459.1:g.36664C>T
NM_002834.3:c.215C>T
NM_080601.1:c.215C>T
NM_001330437.1:c.215C>T
NM_080601.2:c.215C>T
NM_001330437.2:c.215C>T
NM_001374625.1:c.212C>T
NM_002834.5:c.215C>T
NM_080601.3:c.215C>T
ENST00000351677.6:c.215C>T
ENST00000392597.5:c.215C>T
ENST00000635625.1:n.215C>T
More

Pathogenic

Met criteria codes 6
PS3 PP2 PP3 PM1 PM2 PS4_Supporting
Not Met criteria codes 6
BP1 BP4 BP3 BA1 PM4 BS1

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.215C>T (p.Ala72Val) variant in PTPN11 has been reported in 1 patient clinically diagnosed with both Noonan syndrome and juvenile myelomonocytic leukemia (PS4_Supporting; PMID: 30896080). It was absent from large population studies (PM2; gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1, 29493581). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 30896080). Computational prediction tools and conservation analyses also suggest that this 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 variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. RASopathy-specific ACMG/AMP criteria applied: PS3, PS4_Supporting, PM1, PM2, PP2, PP3.
Met criteria codes
PS3
SHP-2 phosphatase assay by Bocchinfuso et al. 2017 (PMID: 17177198) demonstrates increased phosphatase activity for this variant.
This mutant was found to increase the level of baseal phosphatase activity which is an endpoint consistent with PS3 per the RAS VCEP's specifications PubMed:17177198
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.Ala72Val variant may impact the protein (PP3). REVEL score 0.921. This aa is entirely conserved in the UCSC database. Splicing is not predicted to be impacted.
PM1
Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018).
Describes this region as a hotspot PubMed:26619011
RAS VCEP outlines hotspot regions PubMed:29493581
PM2
Absent from both gnomAD v2.1.1 and v3.
PS4_Supporting
Yu et al. 2019 (PMID: 30896080) reported 1 patient clinically diagnosed with both NS and JMML. Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies.
8R, patient with acute lymphoblastic leukemia. Patient was found to have a p.Ile836del variant in FLT3 as well as the p.Ala72Val variant. The FLT3 variant has been identifided as a variant differing between diagnostic and relapse samples. PubMed:20237506
PubMed:30896080
This variant was identified in 2 patients with acute myeloid leukemia via sequencing of 272 AML patients' PTPN11, NRAS, KRAS, NPM1, FLT3/TKD, CEBPA, KIT, AML1 and MLL/PTD. The patient (patient 709) was a 72 year old male who also carried an NPM1 variant that was not described. Patient had normal karyotype Another patient, (patient 811), a 64 year old male with a different FAB subtype, was identified to have this variant and a karyotpye of "no mitosis". Another variant was also identified in NPM1 in this pateint but was not described. PubMed:17972951
Not Met criteria codes
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
BP3
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
PM4
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
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.