rs1554700630

Positions:

• chr9-95482006-G-A
• chr9-95482006-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3 PP5

The NM_000264.5(PTCH1):​c.689C>T​(p.Thr230Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T230P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.60

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 9-95482006-G-A is Pathogenic according to our data. Variant chr9-95482006-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 524591.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}. Variant chr9-95482006-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.689C>T	p.Thr230Ile	missense_variant	5/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.686C>T	p.Thr229Ile	missense_variant	5/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.689C>T	p.Thr230Ile	missense_variant	5/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.686C>T	p.Thr229Ile	missense_variant	5/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Gorlin syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2017	A different missense substitution at this codon (p.Thr230Pro) has been reported as de novo in an individual affected with Gorlin syndrome (PMID: 15459969) and is therefore considered to be pathogenic. This suggests that the threonine residue is critical for PTCH1 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been reported in an individual with suspected Gorlin syndrome in the Leiden Open-source Variation Database (PMID: 21520333). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 230 of the PTCH1 protein (p.Thr230Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 08, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2023

The p.T230I variant (also known as c.689C>T), located in coding exon 5 of the PTCH1 gene, results from a C to T substitution at nucleotide position 689. The threonine at codon 230 is replaced by isoleucine, an amino acid with similar properties. This alteration has been observed in multiple individuals who have a personal or family history that is consistent with PTCH1-associated disease (Ambry internal data). Based on internal structural analysis, the threonine at codon 230 is an important phosphorylation site for protein-protein interactions (Ambry internal structural data; Foord R et al. Nat. Struct. Biol. 1999 Feb;6:157-65; Arnfors L et al. Acta Crystallogr. D Biol. Crystallogr. 2006 Sep;62:1085-97; Cuneo MJ et al. BMC Struct. Biol. 2008 Mar;8:20). In line with the importance of this amino acid residue, two other alterations at this position have been observed in Gorlin Syndrome patients, including in a de novo case: p.T230P and p.T230R (Savino M et al. Hum. Mutat., 2004 Nov;24:441; Reinders MG et al. Mol Genet Genomic Med, 2018 05;6:409-415). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2022

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;.;.;D;.;.;.;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.52		Loss of catalytic residue at T230 (P = 0.0768);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.80
MPC		1.6
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.82
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554700630; hg19: chr9-98244288; COSMIC: COSV59497181; COSMIC: COSV59497181;