Submissions for variant NM_001142864.4(PIEZO1):c.645C>G (p.His215Gln)

gnomAD frequency: 0.00001  dbSNP: rs559847737

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506188	SCV000604657	uncertain significance	not provided	2017-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV000506188	SCV001034820	likely benign	not provided	2024-01-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000506188	SCV001715170	uncertain significance	not provided	2021-07-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002527366	SCV003734990	uncertain significance	Inborn genetic diseases	2022-06-03	criteria provided, single submitter	clinical testing	The c.645C>G (p.H215Q) alteration is located in exon 7 (coding exon 7) of the PIEZO1 gene. This alteration results from a C to G substitution at nucleotide position 645, causing the histidine (H) at amino acid position 215 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003902810	SCV004726427	likely benign	PIEZO1-related condition	2019-08-09	criteria provided, single submitter	clinical testing	This variant is classified as likely 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	RCV000506188	SCV001551486	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PIEZO1 p.His215Gln variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs559847737) and ClinVar (classified as a VUS by ARUP Laboratories). The variant was identified in control databases in 126 of 140580 chromosomes (1 homozygous) at a frequency of 0.0008963 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 125 of 22716 chromosomes (freq: 0.005503) and Other in 1 of 4210 chromosomes (freq: 0.000238), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and European (non-Finnish) populations. The p.His215 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.