Submissions for variant NM_000130.5(F5):c.3455A>C (p.Glu1152Ala)

dbSNP: rs543751483

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000262947	SCV000350908	uncertain significance	Thrombophilia due to activated protein C resistance	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315831	SCV000350909	uncertain significance	Thrombophilia due to thrombin defect	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000262947	SCV000350910	uncertain significance	Thrombophilia due to activated protein C resistance	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000267159	SCV000350911	uncertain significance	Budd-Chiari syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000324603	SCV000350912	uncertain significance	Factor V deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354145	SCV001548687	uncertain significance	not provided		no assertion criteria provided	clinical testing	The F5 p.Glu1152Ala variant is a missense substitution resulting in replacement of a Glutamine (Glu) residue with Alanine (Ala) at codon 1152. The variant was identified in control databases in 41 of 282664 chromosomes (282664 homozygous) at a frequency of 0.000145 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 40 of 20612 chromosomes (freq: 0.000137), Other in 1 of 7216 chromosomes (freq: 0.000139) while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and European (non-Finnish) populations. The variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs543751483) "With Uncertain significance allele" by ClinVar. The variant was also identified in the ClinVar database and called "Uncertain significance" four times by Illumina Clinical Services Laboratory. Clinvar identifies the gene variant to be associated with the following conditions: Factor V Leiden deficiency (synonym: Thrombophilia due to activated protein C resistance), Venous thrombosis and Budd-Chiari syndrome. The variant was also identified in the Clinvitae database. Three out of 5 in silico splicing prediction software programs predict a greater than 10% difference in splicing (SpliceSiteFinder-Like, MaxEntScan, NNSPLICE). Loss of a 3' splice site is predicted at c.3456 (+1 basepair downstream from the variant) by SpliceSiteFinder-Like and gain of a 3' splice site is predicted at c.3461 (+6 basepairs downstream from the variant) by MaxEntScan. The p.Glu1152Ala residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.