Submissions for variant NM_017411.4(SMN2):c.859G>C (p.Gly287Arg)

gnomAD frequency: 0.00208  dbSNP: rs121909192

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
DASA	RCV001824116	SCV002073746	likely pathogenic	Spinal muscular atrophy	2022-02-05	criteria provided, single submitter	clinical testing	The c.859G>C;p.(Gly287Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7962; OMIM: 601627.0001) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SMN) - PM1 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000487481	SCV002769509	likely benign	Kugelberg-Welander disease	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_017411.3(SMN2):c.859G>C, has been identified in exon 8 of 9 of the SMN2 gene. The variant is predicted to result in a major amino acid change from a glycine to an arginine at position 287 of the protein, NP_059107.1(SMN2):p.(Gly287Arg). The glycine residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.32% (519 heterozygous, 140 homozygous). The variant has previously been described to have protective effects in patients with spinal muscular atrophy, whereby a milder form of disease was associated with the presence of this variant in one or two copies of SMN2 (ClinVar, Prior, T., et al. (2009), Bernal, C., et al. (2010), Calucho, M. et al. (2018)). Functional analysis in cells expressing this variant demonstrated a restoration of normal full length transcript to approximately 70% of levels present in SMN1 (Prior, T., et al. (2009)). Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525848	SCV005039397	likely benign	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: SMN2 c.859G>C (p.Gly287Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0031 in 1464442 control chromosomes in the gnomAD database, including 942 homozygotes (gnomAD database v4.0.0). c.859G>C has been described previously to have protective effects in patients with Spinal Muscular Atrophy. This variant, similar to increased copy numbers of SMN2 gene have been correlated with a milder form of disease (e.g. Bernal_2010, Prior_2009). At least one publication reports a significant increase of exon 7 inclusion from 50% to 70% (Prior_2009), which is in agreement with the reported protective effects. The following publications have been ascertained in the context of this evaluation (PMID: 20577007, 19716110). ClinVar contains an entry for this variant (Variation ID: 7962). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000008426	SCV000028634	risk factor	Spinal muscular atrophy, modifier of	2009-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000487481	SCV000574695	not provided	Kugelberg-Welander disease		no assertion provided	literature only