rs121918461
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.182A>C(p.Asp61Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.182A>C | p.Asp61Ala | missense_variant | 3/16 | ENST00000351677.7 | NP_002825.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.182A>C | p.Asp61Ala | missense_variant | 3/16 | 1 | NM_002834.5 | ENSP00000340944 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 09, 2013 | The Asp61Ala variant has not been previously identified by our laboratory, nor h as it been identified in large population studies. This variant has been reporte d in the literature in one fetus with a diagnosis of Noonan syndrome and fetal c hylothorax (Chen 2009). In addition, two other variants at this position have be en identified in >25 individuals with clinical features of Noonan syndrome by ou r laboratory and in the literature (Asp61Asn and Asp61Gly; Loh 2004, Tartaglia 2 005, Tartaglia 2006, Kratz 2005, Yamamoto 2006, Kosaki 2002, Bertola 2006, Noord am 2008, Shaw 2007, Tartaglia 2001). The Asp residue at this position is highly conserved across evolutionarily distinct species, and computational analyses (bi ochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Asp61Ala variant may have impact to the protein. In summary, this variant is l ikely pathogenic, though additional studies are required to fully establish its clinical significance. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2018 | Variant summary: PTPN11 c.182A>C (p.Asp61Ala) results in a non-conservative amino acid change located in the SH2 domain 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 245776 control chromosomes (gnomAD). The variant, c.182A>C, has been reported in the literature in a fetus affected with Noonan Syndrome and Related Conditions (Chen 2009). In addition, other variants affecting this position, Asp61Asn and Asp61Gly, has been reported in several affected individuals. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating an increased basal activity of protein tyrosine phosphatase (OReilly 2000). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at