Submissions for variant NM_000506.3(F2):c.598G>A (p.Glu200Lys)

gnomAD frequency: 0.00138  dbSNP: rs62623459

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000994617	SCV001148249	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108917	SCV001266210	uncertain significance	Congenital prothrombin deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001108918	SCV001266211	benign	Thrombophilia due to thrombin defect	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Neurogenetics Research Program, University of Adelaide	RCV001794445	SCV001737610	risk factor	Cerebral palsy	2021-06-10	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001108917	SCV003244930	likely benign	Congenital prothrombin deficiency	2025-02-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001108918	SCV005399298	uncertain significance	Thrombophilia due to thrombin defect	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Homozygous patients have been shown to have a greater risk for thrombosis than do heterozygotes (PMID: 20301327). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 30297698). (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a condition (332 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting (ClinVar). This variant was originally reported in a patient with prothrombin 3 (PMID: 6405779). More recently, it has been associated with dysprothrombinaemia, however patient presented with normal FII level (PMID: 31352677). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
OMIM	RCV000014229	SCV000034477	pathogenic	PROTHROMBIN TYPE 3	1983-06-01	no assertion criteria provided	literature only
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001108917	SCV002525486	uncertain significance	Congenital prothrombin deficiency		no assertion criteria provided	clinical testing