Submissions for variant NM_001171.6(ABCC6):c.3904G>A (p.Gly1302Arg)

gnomAD frequency: 0.00003  dbSNP: rs63749856

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255838	SCV000321368	pathogenic	not provided	2024-08-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant, located at a position within an ATP binding region of the ABC transporter 2 domain, disrupts the ABCC6-mediated transport of glutathione conjugates (PMID: 11880368); 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: 19133228, 19339160, 16086317, 12673275, 17617515, 32873932, 17251343, 20189652, 32413269, 21179111, 11880368, 29480367, 15727254, 34205333, 11536079, 34906475)
Fulgent Genetics, Fulgent Genetics	RCV000762958	SCV000893396	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2	2024-02-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255838	SCV002023918	likely pathogenic	not provided	2021-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255838	SCV002204985	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1302 of the ABCC6 protein (p.Gly1302Arg). This variant is present in population databases (rs63749856, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 11536079, 16086317, 21179111). ClinVar contains an entry for this variant (Variation ID: 6579). 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 expected to disrupt ABCC6 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000006957	SCV004809525	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000006957	SCV000027153	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2002-10-01	no assertion criteria provided	literature only
PXE International	RCV000006957	SCV000589086	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2021-03-01	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000006957	SCV000607216	not provided	Autosomal recessive inherited pseudoxanthoma elasticum		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
PreventionGenetics, part of Exact Sciences	RCV004737139	SCV005350309	pathogenic	ABCC6-related disorder	2024-09-26	no assertion criteria provided	clinical testing	The ABCC6 c.3904G>A variant is predicted to result in the amino acid substitution p.Gly1302Arg. This variant has been reported in the homozygous and compound heterozygous states in individuals with pseudoxanthoma elasticum (Le Saux et al. 2001. PubMed ID: 11536079; Miksch et al. 2005. PubMed ID: 16086317; Li et al. 2011. PubMed ID: 21179111; Table S1, Boraldi et al. 2021. PubMed ID: 34205333). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.