ClinVar Genomic variation as it relates to human health

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.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Variant summary: PTPN11 c.1449T>G (p.Gly483Gly) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251432 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1449T>G has been reported in the literature as a polymorphism in a validation set used for a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of neuro-cardio-facio-cutaneous syndromes (NCFCS) (example, Justino_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and the ClinGen RASopathy Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as likely benign (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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.