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Variant: NM_002834.4(PTPN11):c.1530G>C (p.Gln510His)

CA220143

40567 (ClinVar)

Gene: PTPN11
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: c1682ae1-ce46-41b9-b916-5efef827298a
Approved on: 2017-04-03
Published on: 2018-12-10

HGVS expressions

NM_002834.4:c.1530G>C
NM_002834.4(PTPN11):c.1530G>C (p.Gln510His)
NC_000012.12:g.112489106G>C
CM000674.2:g.112489106G>C
NC_000012.11:g.112926910G>C
CM000674.1:g.112926910G>C
NC_000012.10:g.111411293G>C
NG_007459.1:g.75375G>C
NM_002834.3:c.1530G>C
NM_001330437.1:c.1542G>C
ENST00000351677.6:c.1530G>C
ENST00000635625.1:n.1542G>C
ENST00000635652.1:n.543G>C
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Pathogenic

Met criteria codes 5
PP3 PP2 PM2 PM6_Strong PM5_Strong

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3). At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344). This variant was absent from large population studies (PM2; ExAC, http://exac.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.Gln510His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM5_Strong, PM2, PP3, PP2.
Met criteria codes
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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).
PM2
This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).
PM6_Strong
The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3).
PM5_Strong
At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344).
Curation History
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