ClinVar Miner

Submissions for variant NM_032861.4(SERAC1):c.1493G>C (p.Ser498Thr)

gnomAD frequency: 0.00003  dbSNP: rs201941476
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809456 SCV000949607 likely pathogenic 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 498 of the SERAC1 protein (p.Ser498Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs201941476, ExAC 0.009%). This variant has been observed in combination with another SERAC1 variant in individuals affected with 3-methylglutaconic aciduria (PMID: 22683713, 29205472, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Kids Research, The Children's Hospital at Westmead RCV000809456 SCV001244737 pathogenic 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome criteria provided, single submitter research
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000809456 SCV001736726 pathogenic 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome 2021-05-20 criteria provided, single submitter clinical testing
GeneDx RCV001779079 SCV002015482 likely pathogenic not provided 2023-09-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32313153, 32827528, 22683713, 34540505, 29205472)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003336206 SCV004046256 likely pathogenic SERAC1-Related Disorders criteria provided, single submitter clinical testing This variant has been previously reported as a compound heterozygous change or together with another SERAC1 variant, phase unknown, in patients with 3-methylglutaconic aciduria (PMID: 29205472, 22683713, 32313153). The c.1493G>C (p.Ser498Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/251074), and is absent in the homozygous state, thus is presumed to be rare. The c.1493G>C (p.Ser498Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1493G>C (p.Ser498Thr) variant is classified as Likely Pathogenic.

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