Submissions for variant NM_152703.5(SAMD9L):c.2069G>A (p.Gly690Asp)

gnomAD frequency: 0.00041  dbSNP: rs147903234

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV001543690	SCV001762387	uncertain significance	Ataxia-pancytopenia syndrome	2021-06-21	criteria provided, single submitter	clinical testing	SAMD9L c.2069G>A (rs147903234) is rare (<0.1%) in a large population dataset (gnomAD: 108/281094 total alleles; 0.04%; no homozygotes) and has been reported in ClinVar (Variation ID: 1049582). Three bioinformatic tools queried predict that this substitution would be damaging and the glycine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of SAMD9L c.2069G>A to be uncertain at this time.
Genetic Services Laboratory, University of Chicago	RCV001820052	SCV002066707	uncertain significance	not specified	2020-12-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SAMD9L gene demonstrated a sequence change, c.2069G>A, in exon 5 that results in an amino acid change, p.Gly690Asp. This sequence change does not appear to have been previously described in individuals with SAMD9L-related disorders and has been described in the gnomAD database with a frequency of 0.066% in the European sub-population (dbSNP rs147903234). The p.Gly690Asp change affects a highly conserved amino acid residue located in a domain of the SAMD9L protein that is not known to be functional. The p.Gly690Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly690Asp change remains unknown at this time.
GeneDx	RCV001355881	SCV002574527	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355881	SCV003257280	likely benign	not provided	2024-12-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224557	SCV003920409	uncertain significance	Monosomy 7 myelodysplasia and leukemia syndrome 1; Ataxia-pancytopenia syndrome; Spinocerebellar ataxia 49	2022-08-23	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in 3 individuals with myelodysplastic syndrome (Sahoo 2021 PMID:34621053). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.07% [84/128246]; https://gnomad.broadinstitute.org/variant/7-92763216-C-T?dataset=gnomad_r2_1), and in ClinVar (Variation ID:1049582). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV004528480	SCV004104064	uncertain significance	SAMD9L-related disorder	2023-07-07	criteria provided, single submitter	clinical testing	The SAMD9L c.2069G>A variant is predicted to result in the amino acid substitution p.Gly690Asp. This variant was reported in an individual with Myelodysplastic syndrome (reported as suppl. Table 6 in Sahoo et al 2021. PubMed ID: 34621053). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92763216-C-T), which may be too common to be causative of disease. While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355881	SCV001550894	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SAMD9L p.Gly690Asp variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs147903234). The variant was identified in control databases in 108 of 281094 chromosomes at a frequency of 0.000384 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 84 of 128246 chromosomes (freq: 0.000655), Latino in 20 of 35320 chromosomes (freq: 0.000566), Other in 4 of 7136 chromosomes (freq: 0.000561), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Gly690 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the G variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001355881	SCV002034931	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001355881	SCV002037305	uncertain significance	not provided		no assertion criteria provided	clinical testing