ClinVar Miner

Submissions for variant NM_006306.4(SMC1A):c.2873A>G (p.Gln958Arg)

dbSNP: rs1253991330
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics, Royal Melbourne Hospital RCV002225221 SCV002503810 uncertain significance Congenital muscular hypertrophy-cerebral syndrome 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to replace glutamine with arginine at codon 958 of the SMC1A protein (p.(Gln958Arg)). The glutamine residue is invariant across species (100 vertebrates, UCSC), and is a critical residue in an ATM kinase substrate motif adjacent to an established phosphoserine in the N terminal domain (PM1; PMID: 11877377, 16273072). There is a small physicochemical difference between glutamine and arginine. The variant is absent in a large population cohort (PM2; gnomAD v2.1, v3.0), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a benign effect for the missense substitution (5/6 algorithms), but the gene is highly missense-constrained. Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM1, PM2.

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