ClinVar Miner

Submissions for variant NM_006940.6(SOX5):c.1678A>G (p.Met560Val)

dbSNP: rs1591908609
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000994876 SCV001148676 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001265682 SCV001443849 likely pathogenic Inborn genetic diseases 2021-06-02 criteria provided, single submitter clinical testing The c.1678A>G (p.M560V) alteration is located in coding exon 13 of the SOX5 gene. This alteration results from an A to G substitution at nucleotide position 1678, causing the methionine (M) at amino acid position 560 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the SOX5 c.1678A>G alteration was not observed, with coverage at this position. This alteration was reported de novo in two unrelated patients (includes this patient) with language delay and mild intellectual disability (Zawerton, 2020). Other features included seizures and temper tantrums. The p.M560 amino acid is conserved in available vertebrate species. The p.M560V amino acid is located in the SOX5 high-mobility group (HMG) domain which is important for DNA binding and bending, nuclear trafficking, and protein-protein interactions (Zawerton, 2020). Functional studies showed that HMG missense variants prevented SOX5 from binding DNA and from participating in transcriptional activation. The p.M560V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV002274106 SCV002559038 pathogenic Neurodevelopmental delay criteria provided, single submitter clinical testing
GeneDx RCV000994876 SCV002818022 pathogenic not provided 2022-12-29 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on DNA binding and activating transcription of gene targets (Zawerton et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31578471)
Institute for Human Genetics, University Hospital Essen RCV000857298 SCV000999892 pathogenic Lamb-Shaffer syndrome 2019-08-05 no assertion criteria provided clinical testing

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