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.1449T>G (p.Gly483=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA134641

44598 (ClinVar)

Gene: PTPN11

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 95a9b0b8-ca1d-4603-93e0-5dfbb46c2c24

Approved on: 2019-08-19

Published on: 2019-12-03

HGVS expressions

NM_002834.4:c.1449T>G

NM_002834.4(PTPN11):c.1449T>G (p.Gly483=)

NC_000012.12:g.112489025T>G

CM000674.2:g.112489025T>G

NC_000012.11:g.112926829T>G

CM000674.1:g.112926829T>G

NC_000012.10:g.111411212T>G

NG_007459.1:g.75294T>G

NM_002834.3:c.1449T>G

NM_001330437.1:c.1461T>G

ENST00000351677.6:c.1449T>G

ENST00000635625.1:n.1461T>G

ENST00000635652.1:n.462T>G

Likely Benign

BP4 BP2 BP7

BP5 PP2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The filtering allele frequency of the c.1449T>G (p.Gly483=) variant in the PTPN11 gene is .01% (13/129134 with CI 95%) of non-Finnish European alleles in gnomAD (BS1 not met). Computational prediction tools and conservation analysis suggest that the p.Gly483= variant does not impact the protein or splicing (BP4). This is a synonymous variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). This variant has been observed with another pathogenic variant in PTPN11 for a fully penetrant dominant gene/disorder (BP2; VCV000013326.4; Laboratory for Molecular Medicine internal data). This variant has been observed in many individuals with varying clinical presentations that lack clear associations with a RASopathy (VCV000013326.4; VCV000045358.1). In summary, the clinical significance of the p.Gly483= variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP2, BP4, BP7.

BP4

No predicted splicing impact, REVEL score not available

BP2

-A 9yo female with Noonan Syndrome. Heterozygous with p.Asn308Asp in PTPN11 (VCV000013326.4) (Laboratory for Molecular Medicine internal data). - A 5 month old individual with Noonan Syndrome. Heterozygous with p.Tyr1008His in SOS1 (VCV000045358.1) (Laboratory for Molecular Medicine internal data).

BP7

Synonymous variant with no predicted splicing impact

BP5

5 mth old, white, het with SOS1 c.3022T>C (p.Tyr1008His), likely pathogenic in ClinVar (VCV000045358.1) (Laboratory for Molecular Medicine internal data). BP5 cannot be applied because the p.Y1008H variant has not been assessed by the ClinGen RASopathy Variant Curation Expert Panel.

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). However, case level data indicates the variant is benign, therefore PP2 is not applied.

Curation History

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