rs199892130

chr9-95468911-A-Cchr9-95468911-A-Gchr9-95468911-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000264.5(PTCH1):c.2090T>G(p.Leu697Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. L697F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.49

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.25370738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.2090T>G	p.Leu697Arg	missense_variant	14/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.2087T>G	p.Leu696Arg	missense_variant	14/24	ENST00000437951.6
LOC100507346	NR_038982.1	n.849A>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.2090T>G	p.Leu697Arg	missense_variant	14/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.2087T>G	p.Leu696Arg	missense_variant	14/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2022

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. 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 PTCH1 protein function. ClinVar contains an entry for this variant (Variation ID: 41653). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 697 of the PTCH1 protein (p.Leu697Arg). -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jul 13, 2012

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2023

The p.L697R variant (also known as c.2090T>G), located in coding exon 14 of the PTCH1 gene, results from a T to G substitution at nucleotide position 2090. The leucine at codon 697 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D;.;.;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.
MutationTaster	Benign	0.53	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.12	T;T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T
Polyphen		0.75	P;B;B;P;P;B;B
Vest4		0.52
MutPred		0.30		Loss of stability (P = 0.0692);.;.;.;.;.;.;
MVP		0.73
MPC		0.89
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs199892130; hg19: chr9-98231193;