ClinVar Miner

Submissions for variant NM_016194.4(GNB5):c.368C>T (p.Ser123Leu) (rs761399728)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000488987 SCV000577012 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing The S123L variant in the GNB5 gene has been reported previously in the homozygous state in two unrelated families with language delay, mild intellectual disability, and bradycardia; as well as a family with severe speech impairment and ADHD (Lodder et al., 2016; Shamseldin et al., 2016). The variant was reported as S81L due to alternate nomenclature (Lodder et al., 2016; Shamseldin et al., 2016). Functional studies showed S123L results in severe but incomplete loss of function, with lower expression levels and significantly impaired activity (Shamseldin et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S123L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S123L as a pathogenic variant.
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000239906 SCV000298234 likely pathogenic Global developmental delay; Delayed speech and language development; Attention deficit hyperactivity disorder 2016-02-02 no assertion criteria provided research
OMIM RCV000258832 SCV000328558 pathogenic Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia 2016-11-09 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000709974 SCV000840338 not provided Intellectual developmental disorder with cardiac arrhythmia; Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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