9-95485685-C-G

Position:

• chr9-95485685-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP5

The NM_000264.5(PTCH1):​c.584G>C​(p.Arg195Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R195K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.15

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-95485685-C-T is described in Lovd as [Pathogenic].
• 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.
• PP5: Variant 9-95485685-C-G is Pathogenic according to our data. Variant chr9-95485685-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453903.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.584G>C	p.Arg195Thr	missense_variant, splice_region_variant	3/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.581G>C	p.Arg194Thr	missense_variant, splice_region_variant	3/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.584G>C	p.Arg195Thr	missense_variant, splice_region_variant	3/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.581G>C	p.Arg194Thr	missense_variant, splice_region_variant	3/24	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:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2023

The c.584G>C variant (also known as p.R195T), located in coding exon 3 of the PTCH1 gene, results from a G to C substitution at nucleotide position 584. The amino acid change results in arginine to threonine at codon 195, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with PTCH1-related disease (external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 28, 2017

A different variant affecting this nucleotide (c.584G>A) has been determined to be pathogenic (PMID: 22434048, 16203740). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. In summary, this variant has uncertain impact on PTCH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a PTCH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with threonine at codon 195 of the PTCH1 protein (p.Arg195Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 3 of the PTCH1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	35
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	0.033
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;.;D;D;.;.;D;.;.;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.98	L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.61	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;D;D;D;D;D;D
Polyphen		0.013	B;.;.;B;B;.;B;.;.;.;.;.;.
Vest4		0.65
MutPred		0.38		Loss of MoRF binding (P = 0.027);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.79
MPC		0.81
ClinPred		0.63	D
GERP RS		5.9
Varity_R		0.54
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -37
DS_DL_spliceai		0.87		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554702009; hg19: chr9-98247967;