ClinVar Miner

Submissions for variant NM_001010892.3(RSPH4A):c.116C>A (p.Ser39Ter)

gnomAD frequency: 0.00003  dbSNP: rs368110732
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825543 SCV000966860 likely pathogenic Primary ciliary dyskinesia 2018-08-23 criteria provided, single submitter clinical testing The p.Ser39X variant in RSPH4A has been reported in one compound heterozygous in dividual and one heterozygous individual without a second variant identified, bo th with primary ciliary dyskinesia (Daniels et al, 2013). This variant has been identified in 5/126582 European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a prem ature termination codon at position 39 which is predicted to lead to a truncated or absent protein. Bialleic loss of function of the RSPH4A gene has been associ ated with primary ciliary dyskinesia. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessi ve carrier frequency. In summary, although additional studies are required to fu lly establish its clinical significance, the p.Ser39X variant in RSPH4A is likel y pathogenic for primary ciliary dyskinesia. ACMG/AMP Criteria applied: PVS1_Str ong, PM2, PM#_Supporting.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV000825543 SCV001431717 pathogenic Primary ciliary dyskinesia 2018-04-26 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV002282387 SCV002570368 pathogenic Primary ciliary dyskinesia 11 2022-08-03 criteria provided, single submitter clinical testing This RSPH4A nonsense variant has been observed in the compound heterozygous state in one individual with primary ciliary dyskinesia, and as a single heterozygous variant without a second variant identified in another unrelated individual with primary ciliary dyskinesia. This variant (rs368110732) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 5/282514 total alleles; 0.0018%; no homozygotes), and has been reported in ClinVar (Variation ID 666983). This nonsense variant results in a premature stop codon in exon 1, likely leading to nonsense-mediated decay and lack of protein production. We consider c.116C>A;p.Ser39Ter in RSPH4A to be pathogenic.
Ambry Genetics RCV000825543 SCV002627023 pathogenic Primary ciliary dyskinesia 2017-01-13 criteria provided, single submitter clinical testing The p.S39* pathogenic mutation (also known as c.116C>A), located in coding exon 1 of the RSPH4A gene, results from a C to A substitution at nucleotide position 116. This changes the amino acid from a serine to a stop codon within coding exon 1. This mutation was described in individuals with primary ciliary dyskinesia, including one individual with a second alteration confirmed in trans (Daniels ML et al. Hum. Mutat., 2013 Oct;34:1352-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV002282387 SCV002809948 pathogenic Primary ciliary dyskinesia 11 2022-04-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000825543 SCV003279219 pathogenic Primary ciliary dyskinesia 2025-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser39*) in the RSPH4A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH4A are known to be pathogenic (PMID: 19200523). This variant is present in population databases (rs368110732, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23798057). ClinVar contains an entry for this variant (Variation ID: 666983). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV004792546 SCV005413748 pathogenic not provided 2024-01-03 criteria provided, single submitter clinical testing PP4, PM3_strong, PVS1

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