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

gnomAD frequency: 0.00001  dbSNP: rs761399728

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000488987	SCV000577012	pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as p.(S123L) results in severe but incomplete loss of function, with lower expression levels and significantly impaired activity (Shamseldin et al., 2016); 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: 27523599, 27677260, 31208990, 32552793, 31589614, 33176815, 30631341, 32280589, 31130284)
Mendelics	RCV000989338	SCV001139629	pathogenic	Gnb5-related intellectual disability-cardiac arrhythmia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000989338	SCV001440580	pathogenic	Gnb5-related intellectual disability-cardiac arrhythmia syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518551	SCV003757436	pathogenic	Inborn genetic diseases	2021-10-20	criteria provided, single submitter	clinical testing	The c.368C>T (p.S123L) alteration is located in exon 4 (coding exon 3) of the GNB5 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the serine (S) at amino acid position 123 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (15/282212) total alleles studied. The highest observed frequency was 0.03% (11/35244) of Latino alleles. This mutation has been reported in the homozygous and compound heterozygous state in several individuals with GNB5-related neurodevelopmental disorder (Lin, 2020; Lodder, 2016; Monies, 2019; Shamseldin, 2016). Functional studies show that this alteration severely impacts dopamine responses (Shamseldin, 2016). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Department Of Translational Genomics (developmental Genetics Section), 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	2023-08-16	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000709974	SCV000840338	not provided	Gnb5-related intellectual disability-cardiac arrhythmia syndrome; 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000488987	SCV001808224	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000989338	SCV001810062	not provided	Gnb5-related intellectual disability-cardiac arrhythmia syndrome		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000488987	SCV001954040	pathogenic	not provided		no assertion criteria provided	clinical testing