SHOC2

Inheritance Pattern: AD

Disease ID:MONDO:0015280

Submitter: ClinGen

Two publications have identified patients with typical features of cardiofaciocutaneous syndrome (CFC) and the p.Ser2Gly variant occuring in de novo cases and cases of unknown variant origin (Lee 2011, Komatsuzaki 2015). However, all of the individuals identified were also described to have loose anagen hair (LAH); therefore, these cases should all be considered SHOC2-Noonan syndrome-like disorder with LAH (NS/LAH) patients. The p.Ser2Gly variant has been a recurrently identified variant in cases with NS/LAH, and no other variants have been identified in these patients (Cordeddu et al., 2009; Ekvall et al., 2011; Komatsuzaki et al., 2010). In summary, this association is Disputed. Of note, SHOC2 is classified as Definitive in association with NS/LAH and as Disputed in association with NS and Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating SHOC2 with NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 6/1/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There have been cases described in the literature with the p.Ser2Gly variant in SHOC2 who were diagnosed with Noonan syndrome (NS) but were not phenotyped for loose anagen hair (LAH) (Hoban, Roberts, Demmer, Jethva, & Shephard, 2012; Justino et al., 2015; Komatsuzaki et al., 2010). There has only been one NS case where LAH was assessed but not noted, and this individual had sparse and curly hair. Therefore, the NS/LAH phenotype cannot be ruled out for any of these patients. The p.Ser2Gly variant has been a recurrently identified variant in cases with NS/LAH, and no other variants have been identified in these patients (Cordeddu et al., 2009; Ekvall et al., 2011; Komatsuzaki et al., 2010). In summary, this association is Disputed. Of note, SHOC2 is classified as Definitive in association with NS-like disorder with loose anagen hair and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating SHOC2 with NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/31/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0009026

Submitter: ClinGen

There have been 2 published cases that were initially diagnosed with suspected Costello syndrome (Komatsuzaki et al., 2010) and the p.S2G variant. However, these individuals also presented with hair anomalies consistent with loose anagen hair, therefore it was concluded both in the paper and by the RASopathy Expert Panel that these cases are more consistent with Noonan-like syndrome with loose anagen hair (NS/LAH). The p.S2G variant has been recurrently identified in cases with NS/LAH (Cordeddu et al., 2009; Ekvall, Hagenas, Allanson, Anneren, & Bondeson, 2011; Komatsuzaki et al., 2010). This association is Disputed. The HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, SHOC2 is classified as Definitive in association with NS/LAH and as Disputed in association with NS and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating SHOC2 with NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

Inheritance Pattern: AD

Disease ID:MONDO:0054637

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011899

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0054637

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0054637

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0054637

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011899

Submitter: ClinGen

There is a definitive association between alteration of the SHOC2 gene and Noonan syndrome with loose anagen hair (NS/LAH). The maximum amount of scorable genetic evidence has been published showing the de novo p.Ser2Gly variant occurs in SHOC2 in patients with NS/LAH (Cordeddu et al., 2009; Galperin, Abdelmoti, & Sorkin, 2012; Motta et al., 2016). Additionally, the p.Met173Ile variant has been identified in one family with disease (Hannig, Jeoung, Jang, Phillips, & Galperin, 2014). The SHOC2 gene is also associated with the Ras/MAPK pathway, which is associated with the NS/LAH phenotype and variants found in NS/LAH patients in this gene disrupt the RAS pathway function as demonstrated by C. elegans models (Cordeddu et al., 2009; Gripp et al., 2016). Of note, SHOC2 is also classified as Disputed in association with NS, cardiofaciocutaneous syndrome, and Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating SHOC2 with NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/25/18 (SOP Version 5).