Submissions for variant NM_002838.5(PTPRC):c.3670G>A (p.Val1224Ile)

gnomAD frequency: 0.00156  dbSNP: rs150672767

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755379	SCV000604988	uncertain significance	not provided	2017-06-23	criteria provided, single submitter	clinical testing	The p.Val1224Ile variant has not been reported in the scientific medical literature or gene specific variant databases. This variant (rs150672767) is listed in the Exome Aggregation Consortium with an overall allele frequency of 0.16 percent. Valine at codon 1224 is weakly conserved considering 10 species (Alamut software v2.7.1), and Orangutan, Rhesus, Baboon, Mouse and Xenopus tropicalis all have isoleucine, suggesting that this amino acid change may be evolutionary tolerated. Additionally, computational analyses do not agree in their assessment of the impact on the protein (PolyPhen2: benign, SIFT: tolerated, and Mutation Taster: disease causing). Thus, even though the conservation and computational data suggest that this variant may represent a benign polymorphism, the clinical significance of p.Val1224Ile variant cannot be determined with certainty. Pathogenic variants in PTPRC are causative for severe combined immunodeficiency (MIM: 608971), and are inherited in autosomal recessive manner. Thus, even if p.Val1224Ile was subsequently determined to be pathogenic, based on the available information, this patient would be a carrier, and may be affected if a second pathogenic PTPRC variant is present on the opposite chromosome but could not be detected by this assay (eg, deep intronic variants, or regulatory region variants).
GeneDx	RCV000755379	SCV000617207	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing	The V1222I variant in the PTPRC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1222I variant is observed in 164/66528 (0.247%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals are reported to be homozygous (Lek et al., 2016). The V1222I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret V1222I as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083271	SCV000761669	benign	Immunodeficiency 104	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755379	SCV001147586	likely benign	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282189	SCV002570732	benign	not specified	2022-07-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000755379	SCV001929396	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000755379	SCV001971923	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925509	SCV004743707	benign	PTPRC-related disorder	2019-09-26	no assertion criteria provided	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).