NM_000193.4:c.1040C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000193.4(SHH):c.1040C>T(p.Pro347Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P347R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SHH
NM_000193.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.17

Publications

4 publications found

Variant links:

Genes affected

SHH (HGNC:10848): (sonic hedgehog signaling molecule) This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]

SHH Gene-Disease associations (from GenCC):

holoprosencephaly 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
microphthalmia, isolated, with coloboma 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
polydactyly of a triphalangeal thumb
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
solitary median maxillary central incisor syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
skeletal system disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypoplastic tibiae-postaxial polydactyly syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
microphthalmia, isolated, with coloboma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndactyly type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
triphalangeal thumb-polysyndactyly syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SHH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000193.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-155803249-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.9479 (below the threshold of 3.09). Trascript score misZ: 0.49525 (below the threshold of 3.09). GenCC associations: The gene is linked to polydactyly of a triphalangeal thumb, microphthalmia, isolated, with coloboma 5, solitary median maxillary central incisor syndrome, holoprosencephaly 3, skeletal system disorder, hypoplastic tibiae-postaxial polydactyly syndrome, holoprosencephaly, syndactyly type 4, microphthalmia, isolated, with coloboma, autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome, triphalangeal thumb-polysyndactyly syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 7-155803249-G-A is Pathogenic according to our data. Variant chr7-155803249-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4 link	c.1040C>T	p.Pro347Leu	missense_variant	Exon 3 of 3	ENST00000297261.7	NP_000184.1	Q15465

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHH	ENST00000297261.7 link	c.1040C>T	p.Pro347Leu	missense_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2	Q15465
SHH	ENST00000430104.5 link	c.302-3004C>T		intron_variant	Intron 3 of 3	1		ENSP00000396621.1	C9JC48
SHH	ENST00000435425.1 link	n.302-2652C>T		intron_variant	Intron 3 of 4	1		ENSP00000413871.1	F8WEH4
SHH	ENST00000441114.5 link	n.302-2582C>T		intron_variant	Intron 3 of 4	1		ENSP00000410546.1	F8WB84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1364358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

675944

African (AFR)

AF:

0.00

AC:

AN:

28354

American (AMR)

AF:

0.00

AC:

AN:

33176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23940

East Asian (EAS)

AF:

0.00

AC:

AN:

31388

South Asian (SAS)

AF:

0.00

AC:

AN:

76090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071930

Other (OTH)

AF:

0.00

AC:

AN:

56502

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Solitary median maxillary central incisor syndrome

Pathogenic:1

Feb 27, 2025

Laboratory of Molecular Genetics, CHU Rennes

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_000193.4:c.1040C>T, is a missense variant in SHH in the Hint domain (PM1), absent from controls (PM2), predicted pathogenic by prediction tools (PP3). This variant inherited (two brothers affected) is probably involved in the pathophysiology of holoprosencephaly according to the oligogenic model described in Kim et al (Brain 2019) and is classified as likely pathogenic. -

SHH-related disorder

Pathogenic:1

Jan 18, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

not provided

Pathogenic:1

Jun 12, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Holoprosencephaly 3

Pathogenic:1

Mar 15, 2017

Muenke lab, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.6

PhyloP100

9.2

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-8.5

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.93

Loss of glycosylation at P347 (P = 0.0258);

MVP

1.0

ClinPred

1.0

GERP RS

3.6

Varity_R

0.99

gMVP

0.96

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over