ClinVar Miner

Submissions for variant NM_000193.4(SHH):c.1040C>T (p.Pro347Leu)

dbSNP: rs886042458
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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 RCV000656532 SCV000778545 pathogenic Holoprosencephaly 3 2017-03-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117460 SCV003800683 pathogenic SHH-related disorder 2023-01-18 criteria provided, single submitter clinical testing Variant summary: SHH c.1040C>T (p.Pro347Leu) results in a non-conservative amino acid change located in the Hint domain (IPR001767) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 130974 control chromosomes (gnomAD). c.1040C>T has been reported in the literature in an individual affected with holoprosencephaly (Roessler_2009, Mercier_2011), and further information submitted to ClinVar from this lab (Muenke lab, National Institutes of Health) has indicated that this was a de novo occurrence. These data suggest that the variant may be associated with holoprosencephaly, a SHH-Related Disorder. A study examining the variant in a zebrafish model found that unlike the wild-type protein, Pro347Leu was unable to rescue the null phenotype, indicating that it impairs protein function. Furthermore, other variants which affect the same residue (e.g. P347R, P347Q) have also been reported in holoproencephaly patients (Roessler_2009, HGMD database). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV004719918 SCV005324845 likely pathogenic not provided 2023-06-12 criteria provided, single submitter clinical testing Identified in a patient with holoprosencephaly in published literature (Roessler et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19603532, 32939873)

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