Submissions for variant NM_000312.4(PROC):c.1321T>C (p.Tyr441His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002663710	SCV002980932	uncertain significance	Thrombophilia due to protein C deficiency, autosomal dominant	2022-06-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 441 of the PROC protein (p.Tyr441His). This variant is present in population databases (rs753436021, gnomAD 0.03%). This missense change has been observed in individual(s) with protein C deficiency (PMID: 7865674). This variant is also known as Tyr399His. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786733	SCV005400067	likely pathogenic	Thrombophilia due to protein C deficiency, autosomal recessive	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant thrombophilia due to protein C deficiency (MIM#176860) and autosomal recessive thrombophilia due to protein C deficiency (MIM#612304). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance is extremely rare and cause life-threatening disorders, whereas autosomal dominant inheritance is more common and leads to increased risk for venous thromboembolism and recurrent thrombosis (PMID: 31821907). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Trypsin-like serine protease domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been previosuly observed as heterozygous in an individual with cerebral palsy and bilateral periventricular white matter hyperintensity on MRI (PMID: 31700678). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function (VCGS). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign