NM_000264.5:c.3328G>C

Variant names:

• chr9-95453599-C-G
• rs911494100
• NM_000264.5:c.3328G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_000264.5(PTCH1):​c.3328G>C​(p.Asp1110His) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1110N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.62
• Publications: 2 publications found

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]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.3328G>C	p.Asp1110His	missense	Exon 20 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3325G>C	p.Asp1109His	missense	Exon 20 of 24	NP_001077072.1
	PTCH1	NM_001354918.2		c.3172G>C	p.Asp1058His	missense	Exon 19 of 23	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.3328G>C	p.Asp1110His	missense	Exon 20 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3325G>C	p.Asp1109His	missense	Exon 20 of 24	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.2875G>C	p.Asp959His	missense	Exon 20 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461546 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Aug 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with histidine at codon 1110 of the PTCH1 protein (p.Asp1110His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Hereditary cancer-predisposing syndrome Uncertain:1

May 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1110H variant (also known as c.3328G>C), located in coding exon 20 of the PTCH1 gene, results from a G to C substitution at nucleotide position 3328. The aspartic acid at codon 1110 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.99	L
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.40		Loss of ubiquitination at K1111 (P = 0.0391)
MVP		0.89
MPC		1.6
ClinPred		0.87	D
GERP RS		5.1
Varity_R		0.49
gMVP		0.77
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs911494100; hg19: chr9-98215881;