Submissions for variant NM_152703.5(SAMD9L):c.3229C>T (p.Arg1077Ter)

dbSNP: rs373868315

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001879861	SCV002140976	uncertain significance	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1077*) in the SAMD9L gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 508 amino acid(s) of the SAMD9L protein. This variant is present in population databases (rs373868315, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SAMD9L-related conditions. ClinVar contains an entry for this variant (Variation ID: 975834). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001879861	SCV003762014	uncertain significance	not provided	2022-07-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Observed by whole genome sequencing in an individual with unspecified clinical history (Stranneheim et al., 2021); This variant is associated with the following publications: (PMID: 33726816)
Clinical Genomics Laboratory, Stanford Medicine	RCV001252956	SCV001427022	uncertain significance	Ataxia-pancytopenia syndrome	2018-11-09	no assertion criteria provided	clinical testing	The p.Arg1077* variant in the SAMD9L gene has not been previously reported in association with disease. The p.Arg1077* variant has been identified in 1/34514 Latino individuals by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Arg1077* variant results in a premature stop codon in the last exon of SAMD9L. Premature termination at this location is not predicted to undergo nonsense-mediated decay, increasing the likelihood of an expressed protein. Previously reported disease-causing variants in SAMD9L are missense variants and are predicted to result in a gain of function mechanism of disease. The p.Arg1077* variant is expected to cause truncation of the protein and therefore the loss of predicted functional domains which may impact the protein function. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg1077* variant is uncertain. Additional information regarding the impact of truncating variants in this gene, and the specific functional impact of this variant is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2, PM4]