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 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. 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. For these reasons, this variant has been classified as Pathogenic.

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