Submissions for variant NM_000313.4(PROS1):c.233C>T (p.Thr78Met)

gnomAD frequency: 0.00002  dbSNP: rs6122

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197958	SCV000253694	pathogenic	Thrombophilia due to protein S deficiency, autosomal recessive	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 78 of the PROS1 protein (p.Thr78Met). This variant is present in population databases (rs6122, gnomAD 0.006%). This missense change has been observed in individuals with PROS1-related conditions (PMID: 7803790, 12351389, 20880255, 22261441, 32964666). This variant is also known as p.Thr37Met. ClinVar contains an entry for this variant (Variation ID: 215991). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PROS1 function (PMID: 12351389). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851742	SCV000899611	likely pathogenic	Protein S deficiency disease	2019-02-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV001781578	SCV002024752	likely pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786532	SCV005400057	likely pathogenic	Thrombophilia due to protein S deficiency, autosomal dominant	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 dominant and recessive thrombophilia due to protein S deficiency (MIM#612336, MIM#614514). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 31335064). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20880255). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (13 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 GLA domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic, and observed in heterozygous individuals with thrombotic events and/or protein S deficiency. Some heterozygous relatives were unaffected, and several probands also carried causative variants in other genes (ClinVar, PMID: 31064749, PMID: 34729451, PMID: 12351389, PMID: 20880255). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 and COS-1 cells demonstrated reduced enzyme activity and protein expression, whereas patient cells showed reduced protein S activity and only slightly reduced free protein S (PMID: 34729451, PMID: 12351389). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV001781578	SCV005413602	likely pathogenic	not provided	2024-08-06	criteria provided, single submitter	clinical testing	PP3, PM2_moderate, PS3, PS4_moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796094	SCV005415723	likely pathogenic	Thrombophilia due to protein S deficiency, autosomal dominant; Thrombophilia due to protein S deficiency, autosomal recessive		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3+PS4_Supporting+PP4+PP1
GeneDx	RCV001781578	SCV005870251	likely pathogenic	not provided	2024-08-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein binding and function (PMID: 12351389); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12351389, 31019026, 31980526, 20981092, 7803790, 22261441, 20880255, 34015304, 34533296, 34729451, 37647632, 36411388, 32964666, 31064749)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851741	SCV000899610	uncertain significance	Deep venous thrombosis	2019-02-01	flagged submission	research
PreventionGenetics, part of Exact Sciences	RCV003917814	SCV004729329	pathogenic	PROS1-related disorder	2024-01-26	no assertion criteria provided	clinical testing	The PROS1 c.233C>T variant is predicted to result in the amino acid substitution p.Thr78Met. This variant, previously described as p.Thr37Met using legacy nomenclature, has been reported in multiple individuals with protein S deficiency (Gandrille et al. 1995. PubMed ID: 7803790; Alhenc-Gelas et al. 2010. PubMed ID: 20880255). Some carriers of this variant were reported to be unaffected or have a mild reduction in the activity of protein S (Alhenc-Gelas et al. 2010. PubMed ID: 20880255; Rezende et al. 2002. PubMed ID: 12351389). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.