ClinVar Miner

Submissions for variant NM_000193.4(SHH):c.1307C>A (p.Ser436Ter)

dbSNP: rs1554493607
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Muenke lab, National Institutes of Health RCV000656536 SCV000778549 pathogenic Holoprosencephaly 3 2017-03-15 criteria provided, single submitter clinical testing
GeneDx RCV002298721 SCV002588064 likely pathogenic not provided 2022-10-25 criteria provided, single submitter clinical testing Reported in an individual with alobar holoprosencephaly and a complex heart defect and in another individual with holoprosencephaly and a single central incisor. Variant was inherited for both individuals; no clinical information was provided for the parents (Tekendo-Ngongang et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 27 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 32022405)
Labcorp Genetics (formerly Invitae), Labcorp RCV000656536 SCV003031525 pathogenic Holoprosencephaly 3 2023-06-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the SHH protein. Other variant(s) that disrupt this region (p.Q437*) have been observed in individuals with SHH-related conditions (PMID: 15942944). This suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 545579). This premature translational stop signal has been observed in individuals with holoprosencephaly (PMID: 32022405). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser436*) in the SHH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the SHH protein.

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