Submissions for variant NM_002834.5(PTPN11):c.1530G>C (p.Gln510His)

dbSNP: rs397507550

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000521890	SCV000616416	pathogenic	RASopathy	2017-04-03	reviewed by expert panel	curation	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.
GeneDx	RCV000077854	SCV000057460	pathogenic	not provided	2022-01-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 24234437, 25232094, 31263281, 31560489, 33318624, 31277675, 21910226)
Eurofins Ntd Llc (ga)	RCV000077854	SCV000331072	likely pathogenic	not provided	2015-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000521890	SCV000918110	pathogenic	RASopathy	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1530G>C (p.Gln510His) results in a non-conservative amino acid change affecting a critical amino acid located in the PTP type protein phosphatase of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 30972 control chromosomes. c.1530G>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One was the "ClinGen RASopathy Expert Panel" which classified this variant as Pathogenic, while the other classified it as "Likely Pathogenic" without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000077854	SCV002019550	pathogenic	not provided	2019-11-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399355	SCV002705518	pathogenic	Cardiovascular phenotype	2023-02-28	criteria provided, single submitter	clinical testing	The p.Q510H pathogenic mutation (also known as c.1530G>C), located in coding exon 13 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1530. The glutamine at codon 510 is replaced by histidine, an amino acid with highly similar properties. This variant as been reported in multiple individuals with PTPN11-related RASopathy (Wakabayashi Y et al. Am. J. Med. Genet. A, 2011 Oct;155A:2529-33; Chinton J et al. Arch Argent Pediatr, 2019 Oct;117:330-337; Kauffman H et al. Pediatr Res, 2021 Aug;90:444-451). It has also been determined to be the result of a de novo mutation in a fetus with features including hydrops fetalis, pleural effusion, cardiomyopathy, and hepatomegaly (Stuurman KE et al. J Med Genet, 2019 Oct;56:654-661). Another variant at the same codon, c.1530G>T (p.Q510H), has been described previously in fetuses with cystic hygroma (Gezdirici A et al. J Matern Fetal Neonatal Med, 2017 Apr;30:938-941). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002490449	SCV002798295	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-12-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147313	SCV003835319	pathogenic	Metachondromatosis	2022-08-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147314	SCV003835376	pathogenic	LEOPARD syndrome 1	2022-08-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147312	SCV003836404	pathogenic	Noonan syndrome 1	2022-08-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532497	SCV004749545	pathogenic	PTPN11-related disorder	2023-12-29	criteria provided, single submitter	clinical testing	The PTPN11 c.1530G>C variant is predicted to result in the amino acid substitution p.Gln510His. This variant has been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (Table 1, Wakabayashi et al. 2011. PubMed ID: 21910226; Table 3, Chinton et al. 2019. PubMed ID: 31560489; Table S2, Kauffman et al. 2020. PubMed ID: 33318624). Moreover, this variant has been reported as having arisen de novo in an individual with Noonan syndrome with multiple lentigines (Table 1, Li et al. 2019. PubMed ID: 31263281). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40567/). Alternate nucleotide changes affecting the same amino acid (p.Gln510Glu, p.Gln510Pro, and p.Gln510Arg) have been reported in multiple individuals with Noonan syndrome with or without multiple lentigines (Digilio et al. 2006. PubMed ID: 16733669; Keren et al. 2004. PubMed ID: 15520399; Bertola et al. 2005. PubMed ID: 15948193). In summary, the p.Gln510His variant is interpreted as pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV003147312	SCV004847164	pathogenic	Noonan syndrome 1	2023-04-20	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000077854	SCV002036872	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000077854	SCV002037336	pathogenic	not provided		no assertion criteria provided	clinical testing