Submissions for variant NM_002838.5(PTPRC):c.3545T>C (p.Leu1182Ser)

gnomAD frequency: 0.00025  dbSNP: rs114970039

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171165	SCV000221361	likely pathogenic	not provided		criteria provided, single submitter	research
Invitae	RCV000696429	SCV000824991	uncertain significance	Immunodeficiency 104	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1182 of the PTPRC protein (p.Leu1182Ser). This variant is present in population databases (rs114970039, gnomAD 0.04%). This missense change has been observed in individual(s) with combined immunodeficiency (PMID: 26915675). This variant is also known as c.T3062C, p.L1021S. ClinVar contains an entry for this variant (Variation ID: 190992). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000696429	SCV000898922	uncertain significance	Immunodeficiency 104	2018-06-08	criteria provided, single submitter	clinical testing	PTPRC NM_002838.4 exon 32 p.Leu1182Ser (c.3545T>C): This variant has been reported in the literature as homozygous in 1 individual with combined immunodeficiency (Al-Mousa 2016 PMID:26915675). This variant is present in 53/126002 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs114970039). This variant is present in ClinVar (Variation ID:190992). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Baylor Genetics	RCV000696429	SCV001522581	uncertain significance	Immunodeficiency 104	2019-08-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002485087	SCV002783330	uncertain significance	Immunodeficiency 104; Hepatitis C virus, susceptibility to	2022-02-18	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224185	SCV003920371	uncertain significance	Immunodeficiency 105	2021-03-30	criteria provided, single submitter	clinical testing	PTPRC NM_002838.4 exon 32 p.Leu1182Ser (c.3545T>C): This variant has been reported in the literature as homozygous in 1 individual with combined immunodeficiency (Al-Mousa 2016 PMID:26915675). This variant is present in 53/126002 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs114970039). This variant is present in ClinVar (Variation ID:190992). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987396	SCV004803264	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: PTPRC c.3545T>C (p.Leu1182Ser) results in a non-conservative amino acid change located in the Tyrosine-specific protein phosphatase, PTPase domain (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 250448 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PTPRC causing Severe Combined Immunodeficiency (0.00025 vs 0.00035), although the frequency in non-Finnish Europeans (0.00043) is slighly higher than estimated. c.3545T>C has been reported in the literature in a homozygous individual affected with Combined Immunodeficiency (Al-Mousa_2016). This report does not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26915675). ClinVar contains an entry for this variant (Variation ID: 190992). Based on the evidence outlined above, the variant was classified as uncertain significance.