rs121909565

Variant names:

• chr1-173909564-A-G
• rs121909565
• NM_000488.4:c.1141T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_Supporting PS4_Supporting PP3 PP1

This summary comes from the ClinGen Evidence Repository: The c.1141T>C variant in SERPINC1 is a missense variant predicted to cause substitution of serine by proline at amino acid 381 (p.Ser381Pro). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. Only one had a family history of disease supported with reported antithrombin activity levels (PS4_Supporting; PMIDs: 1551681, 30975910). The variant has been reported to segregate with hereditary antithrombin deficiency in two affected meioses from one family (PP1; PMID:1551681). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.616, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3).In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PP3, PM2_Supporting, PS4_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) LINK:https://erepo.genome.network/evrepo/ui/classification/CA210783/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 2.72

Genes affected

SERPINC1 (HGNC:775): (serpin family C member 1) The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.1141T>C	p.Ser381Pro	missense_variant	Exon 5 of 7	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1141T>C	p.Ser381Pro	missense_variant	Exon 5 of 7	1	NM_000488.4	ENSP00000356671.3
SERPINC1	ENST00000487183.1	n.*166T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:2 Uncertain:1

Dec 20, 2024

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1141T>C variant in SERPINC1 is a missense variant predicted to cause substitution of serine by proline at amino acid 381 (p.Ser381Pro). This variant has been reported in 2 probands meeting an antithrombin activity level of < 0.8 IU/mL. Only one had a family history of disease supported with reported antithrombin activity levels (PS4_Supporting; PMIDs: 1551681, 30975910). The variant has been reported to segregate with hereditary antithrombin deficiency in two affected meioses from one family (PP1; PMID:1551681). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.616, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PP3, PM2_Supporting, PS4_Supporting. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) -

Nov 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 381 of the SERPINC1 protein (p.Ser381Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant antithrombin deficiency (PMID: 1551681, 30975910). It has also been observed to segregate with disease in related individuals. This variant is also known as Ser349Pro. ClinVar contains an entry for this variant (Variation ID: 18032). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINC1 protein function with a negative predictive value of 80%. This variant disrupts the p.Ser381 amino acid residue in SERPINC1. Other variant(s) that disrupt this residue have been observed in individuals with SERPINC1-related conditions (PMID: 29153735), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.80	P
Vest4		0.77
MutPred		0.87		Gain of catalytic residue at S381 (P = 0.0252);
MVP		0.92
MPC		0.82
ClinPred		0.91	D
GERP RS		1.9
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909565; hg19: chr1-173878702;