rs397516805
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP5BS1
This summary comes from the ClinGen Evidence Repository: The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). 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 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Université Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134665/MONDO:0021060/004
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.392A>G | p.Lys131Arg | missense_variant | 4/16 | ENST00000351677.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.392A>G | p.Lys131Arg | missense_variant | 4/16 | 1 | NM_002834.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251376Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135852
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461164Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726892
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 12, 2011 | The Lys131Arg variant in PTPN11 has been reported in the literature in one Chine se individual with clinical features of Noonan syndrome (Chan 2006). This varian t was identified in that individual's mother; however clinical features for the mother were not provided. In addition, this variant has been detected by our lab oratory in one Asian proband who also has a pathogenic MEK1 variant. The Lys131 residue is highly conserved across mammals and lower species and computational a nalyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Lys131Arg variant may impa ct the normal function of PTPN11. Given this information, we are unable to make a conclusive determination as to whether this variant is responsible for the cli nical features observed in this individual. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2024 | Variant summary: PTPN11 c.392A>G (p.Lys131Arg) results in a conservative amino acid change located in the SH2 domain 2 (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251376 control chromosomes, predominantly at a frequency of 0.00065 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome And Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.392A>G, has been reported in the literature in Chinese individuals, who were affected with Noonan Syndrome and Related Conditions (Chan_2006, Yu_2019), however without providing supportive evidence for causality. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. In addition, the variant was also reported in healthy individuals of East Asian ancestry (Bodian_2014). ClinVar contains an entry for this variant (Variation ID: 44607). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Noonan syndrome Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Mar 08, 2017 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2020 | This variant is associated with the following publications: (PMID: 30896080, 24728327) - |
RASopathy Benign:2
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Aug 19, 2019 | The c.392A>G (p.Lys131Arg) variant in the PTPN11 gene has been identified in a patient with an alternate molecular basis of disease (BP5; Laboratory for Molecular Medicine internal data; VCV000013351.2, GeneDx internal data; VCV000013351.2). The filtering allele frequency of p.Lys131Arg variant is 0.042% for East Asian alleles in the gnomAD database (14/19952 with 95% CI), which is a high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). 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 not met due to case level data indicative of benign). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2 not met; Universite Paris Diderot internal data). The ClinGen RASopathy Expert Panel has classified the p.Lys131Arg variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
PTPN11-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 14, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at