Submissions for variant NM_001171.6(ABCC6):c.3340C>T (p.Arg1114Cys)

gnomAD frequency: 0.00004  dbSNP: rs63749794

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857045	SCV002231990	pathogenic	not provided	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1114 of the ABCC6 protein (p.Arg1114Cys). This variant is present in population databases (rs63749794, gnomAD 0.03%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 15459974, 16086317). ClinVar contains an entry for this variant (Variation ID: 433307). 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%. This variant disrupts the p.Arg1114 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16835894, 18157818, 18513494). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002489227	SCV002776324	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2	2024-06-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001857045	SCV004170291	likely pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16086317, 22209248, 15459974, 31589614, 28912966, 32873932, 32039214, 34205333, 34906475, 16835894)
Neuberg Centre For Genomic Medicine, NCGM	RCV000499109	SCV004171968	likely pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2023-01-24	criteria provided, single submitter	clinical testing	The missense c.3340C>T (p.Arg1114Cys) variant in ABCC6 gene has been reported previously in individuals affected with pseudoxanthoma elasticum (Gheduzzi et al. 2004; Miksch et al. 2005; Verschuere et al. 2021). The p.Arg1114Cys variant is reported with an allele frequency of 0.009% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Arg1114Cys in ABCC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 1114 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Another missense [c.3341G>A | p.Arg1114His] variant at this residue has previously been classified as pathogenic. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001857045	SCV005042255	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ABCC6: PM3:Strong, PM1, PM2, PM5
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000499109	SCV005438432	likely pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2024-12-18	criteria provided, single submitter	clinical testing
PXE International	RCV000499109	SCV000589044	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2021-03-01	no assertion criteria provided	research