Submissions for variant NM_015991.4(C1QA):c.11C>G (p.Pro4Arg)

gnomAD frequency: 0.00023  dbSNP: rs149230484

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001969029	SCV002253296	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the C1QA protein (p.Pro4Arg). This variant is present in population databases (rs149230484, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with C1QA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1468526). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471205	SCV002767740	uncertain significance	C1Q deficiency	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_015991.2(C1QA):c.11C>G in exon 2 of 3 of the C1QA gene. This substitution is predicted to create a major amino acid change from proline to arginine at position 4 of the protein, NP_057075.1(C1QA):p.(Pro4Arg). The proline at this position has low conservation (100 vertebrates, UCSC), and is located within the signal peptide motif. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.02% (68 heterozygotes, 0 homozygotes). An alternative residue change to serine at the same location has been reported in the gnomAD database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). The variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).