Submissions for variant NM_017654.4(SAMD9):c.2054G>A (p.Arg685Gln)

dbSNP: rs1064795431

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479048	SCV000571229	pathogenic	not provided	2024-03-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: transfection of the R685Q mutant protein in HEK293 cells has a gain-of-function effect and protein expression is decreased in fibroblasts relative to wildtype controls (PMID: 28346228); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28346228, Panaitescu2024[Review], 31309983)
Ambry Genetics	RCV002525885	SCV003632202	pathogenic	Inborn genetic diseases	2022-07-13	criteria provided, single submitter	clinical testing	The c.2054G>A (p.R685Q) alteration is located in exon 3 (coding exon 1) of the SAMD9 gene. This alteration results from a G to A substitution at nucleotide position 2054, causing the arginine (R) at amino acid position 685 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported as de novo in a patient with intrauterine growth restriction, severe adrenal insufficiency, intraabdominal gonads, anemia, thrombocytopenia, blood infection/sepsis, and respiratory distress syndrome/bronchopulmonary dysplasia. Hematopoietic cells showed monosomy 7 and then partial loss of 7q. The patient died at 21 months of age (Buonocore, 2017). This alteration was reported in an additional patient with myelodysplastic syndrome/myeloproliferative neoplasm showing monosomy 7 on morphological evaluation of bone marrow (Weinberg, 2019). This amino acid position is not well conserved in available vertebrate species. Functional analysis demonstrated that the p.R685Q alteration reduced cell proliferation compared to controls, consistent with a gain-of-function effect (Buonocore, 2017). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387520	SCV004099222	pathogenic	MIRAGE syndrome	2023-07-19	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM2, PM6
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479048	SCV005835316	likely pathogenic	not provided	2024-06-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 685 of the SAMD9 protein (p.Arg685Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant MIRAGE syndrome (PMID: 28346228). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SAMD9 protein function. Experimental studies have shown that this missense change affects SAMD9 function (PMID: 28346228). 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.