Submissions for variant NM_152703.5(SAMD9L):c.4144A>G (p.Asn1382Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003828329	SCV004623567	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	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) performed at Invitae indicates that this missense variant is expected to disrupt SAMD9L protein function. This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1382 of the SAMD9L protein (p.Asn1382Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SAMD9L-related conditions. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594713	SCV005087034	uncertain significance	Ataxia-pancytopenia syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Toxic gain of function is the postulated mechanism for ataxia-pancytopenia syndrome (MIM#159550; PMID: 28570036), while monosomy 7 myelodysplasia and leukaemia syndrome 2 (MIM#619041) is the result of a somatic compensatory mechanism (PMID: 34621053). The mechanism for spinocerebellar ataxia 49 (MIM#619806) is unknown; however, protein reduction in the mitochondrial fraction of fibroblasts from an affected individual was observed (PMID: 35310830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable haematologic and neurologic manifestations have been reported (PMID: 28570036). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign