Submissions for variant NM_003738.5(PTCH2):c.1864C>A (p.His622Asn)

dbSNP: rs11573586

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238650	SCV000297049	likely benign	not specified	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000463987	SCV000560012	benign	Gorlin syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001358410	SCV002005963	likely benign	not provided	2020-10-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001358410	SCV004123744	benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	PTCH2: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003967677	SCV004780564	benign	PTCH2-related condition	2020-02-18	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358410	SCV001554134	likely benign	not provided		no assertion criteria provided	clinical testing	The PTCH2 p.His622Asn variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs11573586), LOVD 3.0 (classified as likely benign) and in ClinVar (classified as likely benign by Division of Genomic Diagnostics, The Children's Hospital of Philadelphia and as benign by Invitae). The variant was also identified in control databases in 644 of 282218 chromosomes (1 homozygous) at a frequency of 0.002282 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: European (Finnish) in 180 of 25086 chromosomes (freq: 0.007175), European (non-Finnish) in 416 of 128572 chromosomes (freq: 0.003236), Other in 12 of 7220 chromosomes (freq: 0.001662), African in 29 of 24968 chromosomes (freq: 0.001161) and Latino in 7 of 35434 chromosomes (freq: 0.000198), while the variant was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.His622 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001358410	SCV001800465	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000238650	SCV001807238	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001358410	SCV001972493	likely benign	not provided		no assertion criteria provided	clinical testing