NM_000062.3(SERPING1):c.589C>G (p.Leu197Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000483273.3

Allele description [Variation Report for NM_000062.3(SERPING1):c.589C>G (p.Leu197Val)]

NM_000062.3(SERPING1):c.589C>G (p.Leu197Val)

Gene:

SERPING1:serpin family G member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q12.1

Genomic location:

Preferred name:

NM_000062.3(SERPING1):c.589C>G (p.Leu197Val)

HGVS:

NC_000011.10:g.57602073C>G
NG_009625.1:g.9520C>G
NM_000062.3:c.589C>GMANE SELECT
NM_001032295.2:c.589C>G
NP_000053.2:p.Leu197Val
NP_000053.2:p.Leu197Val
NP_001027466.1:p.Leu197Val
LRG_105t1:c.589C>G
LRG_105:g.9520C>G
LRG_105p1:p.Leu197Val
NC_000011.9:g.57369546C>G
NM_000062.2:c.589C>G

Protein change:

L197V

Links:

dbSNP: rs1064793266

NCBI 1000 Genomes Browser:

rs1064793266

Molecular consequence:

NM_000062.3:c.589C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001032295.2:c.589C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Gene
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RIOK3 [Pan paniscus]
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Gene
K.lactis kex1 gene
K.lactis kex1 gene
gi|2834|emb|X07038.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000565554	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 29, 2016)	germline	clinical testing	Citation Link,
SCV004499654	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31517426, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000565554

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 29, 2016)

germline

clinical testing

Citation Link,

SCV004499654

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 22, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SERPING1 mutation update: Mutation spectrum and C1 Inhibitor phenotypes.

Ponard D, Gaboriaud C, Charignon D, Ghannam A, Wagenaar-Bos IGA, Roem D, López-Lera A, López-Trascasa M, Tosi M, Drouet C.

Hum Mutat. 2020 Jan;41(1):38-57. doi: 10.1002/humu.23917. Epub 2019 Oct 22. Review.

PubMed [citation]

PMID:: 31517426

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000565554.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The L197V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. L197V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004499654.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 197 of the SERPING1 protein (p.Leu197Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary angioedema type I (PMID: 31517426). ClinVar contains an entry for this variant (Variation ID: 418485). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPING1 protein function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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