Submissions for variant NM_017654.4(SAMD9):c.2945G>A (p.Arg982His)

dbSNP: rs1554336974

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000677708	SCV000803860	likely pathogenic	MIRAGE syndrome	2016-11-01	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000677708	SCV001364302	pathogenic	MIRAGE syndrome	2020-05-15	criteria provided, single submitter	research	ACMG codes: PS2, PS3, PM2, PP4
GeneDx	RCV001662742	SCV001872888	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect: gain of function variant resulting in decreased cell proliferation (Buonocore et al., 2017); 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; This variant is associated with the following publications: (PMID: 31231135, 29217778, 28346228, 34258490, 34930662, 28545555, 27535533)
Invitae	RCV001662742	SCV002257951	likely pathogenic	not provided	2021-02-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 982 of the SAMD9 protein (p.Arg982His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant has been observed in individual(s) with clinical features of MIRAGE syndrome (PMID: 28346228, 31231135, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 559913). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg982 amino acid residue in SAMD9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28346228). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
Diagnostic and Treatment Unit for Congenital Metabolic Diseases, Hopital Clínico Universitario de Santiago de Compostela (CHUS)	RCV000677708	SCV002524124	likely pathogenic	MIRAGE syndrome	2021-11-10	no assertion criteria provided	clinical testing