ClinVar Miner

Submissions for variant NM_000193.4(SHH):c.676G>A (p.Ala226Thr)

gnomAD frequency: 0.00006  dbSNP: rs104894043
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000009433 SCV001210478 likely pathogenic Holoprosencephaly 3 2023-07-19 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 8883). This missense change has been observed in individuals with midline defects (PMID: 9302262, 22897141, 29205322). This variant is present in population databases (rs104894043, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 226 of the SHH protein (p.Ala226Thr). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHH protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects SHH function (PMID: 15292211, 22897141).
CeGaT Center for Human Genetics Tuebingen RCV001092783 SCV001249440 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Laboratory of Human Genetics, Universidade de São Paulo RCV001813967 SCV002060423 uncertain significance Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies 2019-01-16 criteria provided, single submitter research Maternal inheritance. Presence of the variant confirmed by sanger in one sister and absent in the other. SHH pathogenic variants have incomplete penetrance and variable expressivity. Further, the phenotype is not suggestive of variants in this gene.
OMIM RCV000009433 SCV000029651 pathogenic Holoprosencephaly 3 1997-10-01 no assertion criteria provided literature only
GeneReviews RCV000009433 SCV000087214 pathologic Holoprosencephaly 3 2013-08-29 no assertion criteria provided curation Converted during submission to Pathogenic.

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