ClinVar Miner

Submissions for variant NM_001355436.2(SPTB):c.4973+5G>A

dbSNP: rs1555367789
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de Paris RCV000655910 SCV000777859 likely pathogenic Hereditary spherocytosis type 2 2018-02-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001379964 SCV001577880 pathogenic not provided 2024-07-12 criteria provided, single submitter clinical testing This sequence change falls in intron 23 of the SPTB gene. It does not directly change the encoded amino acid sequence of the SPTB protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with spherocytosis (PMID: 29572776, 31807509; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 544813). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001379964 SCV001714477 likely pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing PS4_moderate, PM2, PP3, PP5
Revvity Omics, Revvity RCV001379964 SCV003815410 likely pathogenic not provided 2022-09-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001379964 SCV005877207 likely pathogenic not provided 2024-01-02 criteria provided, single submitter clinical testing The SPTB c.4973+5G>A variant (rs1555367789) is reported in the literature in three individuals affected with hereditary spherocytosis (Mansour-Hendili 2020, Wang 2018, Xue 2019), including once as a de novo mutation. This variant is also reported in ClinVar (Variation ID: 544813). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Mansour-Hendili L et al. Exome sequencing for diagnosis of congenital hemolytic anemia. Orphanet J Rare Dis. 2020 Jul 8. PMID: 32641076. Wang R et al. Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis. Sci China Life Sci. 2018 Aug. PMID: 29572776. Xue J et al. Clinical utility of targeted gene enrichment and sequencing technique in the diagnosis of adult hereditary spherocytosis. Ann Transl Med. 2019 Oct. PMID: 31807509.

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