NM_000064.4(C3):c.193A>C (p.Lys65Gln) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: May 12, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV000427027.12

Allele description [Variation Report for NM_000064.4(C3):c.193A>C (p.Lys65Gln)]

NM_000064.4(C3):c.193A>C (p.Lys65Gln)

Gene:

C3:complement C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_000064.4(C3):c.193A>C (p.Lys65Gln)

Other names:

p.Lys65Gln

HGVS:

NC_000019.10:g.6719285T>G
NG_009557.1:g.6367A>C
NM_000064.4:c.193A>CMANE SELECT
NP_000055.2:p.Lys65Gln
LRG_27:g.6367A>C
NC_000019.9:g.6719296T>G
NM_000064.3:c.193A>C

Protein change:

K65Q

Links:

dbSNP: rs539992721

NCBI 1000 Genomes Browser:

rs539992721

Molecular consequence:

NM_000064.4:c.193A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000521327	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 29, 2024)	germline	clinical testing	Citation Link,
SCV002298601	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 2, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30046676, 33609329, 35372954, 22669319, 25608561, 28492532
SCV007136805	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 12, 2025)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 15304516, 22669319, 23307876, 24038559, 24736606, 25608561, 25899302, 28941939, 29888403, 30046676, 30659006, 30916388, 33609329, 33841858, 34169201, 37369098, 37744338, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000521327

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 29, 2024)

germline

clinical testing

Citation Link,

SCV002298601

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 2, 2025)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV007136805

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 12, 2025)

germline

clinical testing

PubMed (18)
[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	7	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Beyond Panel-Based Testing: Exome Analysis Increases Sensitivity for Diagnosis of Genetic Kidney Disease.

Wilson PC, Love-Gregory L, Corliss M, McNulty S, Heusel JW, Gaut JP.

Kidney360. 2020 Aug 27;1(8):772-780. doi: 10.34067/KID.0001342020.

PubMed [citation]

PMID:: 35372954
PMCID:: PMC8815744

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

See all PubMed Citations (20)

Details of each submission

From GeneDx, SCV000521327.8

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

Description

Reported multiple times in the heterozygous state in possible association with atypical hemolytic-uremic syndrome, however, detailed clinical and segregation information was not provided in all instances (PMID: 22669319, 25899302, 30046676, 34169201, 33841858); Published functional studies demonstrate that this alteration leads to decreased binding of C3b to CFH in vitro and modest but significant decreases in factor F and membrane cofactor protein association rate and binding affinity compared to wild type (PMID: 22669319, 25608561); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22669319, 36631797, 37744338, 25608561, 24736606, 31589614, 30046676, 33609329, 25899302, 34169201, 33841858, 37567446, 35385571, 32765494, 29888403, 24799305, 23852337, 28025630, 24853370, 25188723, 24038559, 30225264, 34631043)

#	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, SCV002298601.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 65 of the C3 protein (p.Lys65Gln). This variant is present in population databases (rs539992721, gnomAD 0.009%). This missense change has been observed in individuals with atypical hemolytic uremic syndrome (PMID: 22669319, 25608561, 30046676, 33609329, 35372954). This variant is also known as K43Q. ClinVar contains an entry for this variant (Variation ID: 381739). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt C3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects C3 function (PMID: 22669319, 25608561). 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.

#	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

From Mayo Clinic Laboratories, Mayo Clinic, SCV007136805.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (18)

Description

PP3, PS3, PS4

#	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		7	not provided	not provided	not provided

Last Updated: Jan 11, 2026

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