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NM_000488.4(SERPINC1):c.624+1G>A AND Hereditary antithrombin deficiency

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jan 25, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000856668.5

Allele description [Variation Report for NM_000488.4(SERPINC1):c.624+1G>A]

NM_000488.4(SERPINC1):c.624+1G>A

Gene:
SERPINC1:serpin family C member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q25.1
Genomic location:
Preferred name:
NM_000488.4(SERPINC1):c.624+1G>A
Other names:
p.?
HGVS:
  • NC_000001.11:g.173911798C>T
  • NG_012462.1:g.10581G>A
  • NM_000488.4:c.624+1G>AMANE SELECT
  • NM_001365052.2:c.480+1G>A
  • NM_001386302.1:c.624+1G>A
  • NM_001386303.1:c.705+1G>A
  • NM_001386304.1:c.624+1G>A
  • NM_001386305.1:c.624+1G>A
  • NM_001386306.1:c.409-907G>A
  • LRG_577t1:c.624+1G>A
  • LRG_577:g.10581G>A
  • NC_000001.10:g.173880936C>T
  • NM_000488.3:c.624+1G>A
Links:
dbSNP: rs1572090079
NCBI 1000 Genomes Browser:
rs1572090079
Molecular consequence:
  • NM_001386306.1:c.409-907G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000488.4:c.624+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001365052.2:c.480+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001386302.1:c.624+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001386303.1:c.705+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001386304.1:c.624+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001386305.1:c.624+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
Hereditary antithrombin deficiency (AT3D)
Synonyms:
Antithrombin III deficiency; Thrombophilia due to antithrombin III deficiency; Reduced antithrombin III activity; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0013144; MedGen: C0272375; OMIM: 613118; Human Phenotype Ontology: HP:0001976

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000998941Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 8, 2019)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005061629Clingen Thrombosis Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen ACMG Specifications SERPINC1 V1.0.0)
Likely Pathogenic
(Jan 25, 2024)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology, SCV000998941.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (1)

Description

The variant causes alteration of a wild type donor splice-site. The c.624+1G>A variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP. The variant is also not present in our in-house exome database. The variant was also not reported to OMIM, ClinVar and Human Genome Mutation Database (HGMD) in any other affected individuals. However a different base change (c.624+1G>T) in the same position was reported in HGMD (ID: CS126235) in similarly affected individuals . In-silico pathogenicity prediction programs like Mutation Taster2, CADD etc. predicted this variant as likely disease causing.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Clingen Thrombosis Variant Curation Expert Panel, ClinGen, SCV005061629.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.624+1G>A (NM_000488.4) variant in SERPINC1 occurs within the canonical splice donor site (+1) of intron 3. The variant is not predicted to disrupt reading frame, the role of the region is unknown, LoF variants are not common in SERPINC1, the variant is present in transcript NM_000488.4, and is predicted to affect >10% of the protein (15% (71AA in Exon 3/464AA total)) meeting criteria for PVS1_Strong.The variant is absent from gnomAD v2.1.1 and v3.1 with good coverage across both genomes and exomes, meeting criteria for PM2_supporting. This variant has been reported in 1 proband with antithrombin activity level of 55 meeting the SERPINC1-phenotypic criteria (AT level of <0.8 IU/mL) (PS4_Supporting; Alhenc-Gelas et al. 2017. PMID: 28300866). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for AT Deficiency for SERPINC1: PVS1_Strong, PS4_Supporting, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 28, 2024