Submissions for variant NM_001171.6(ABCC6):c.3412C>T (p.Arg1138Trp)

gnomAD frequency: 0.00004  dbSNP: rs28939701

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255802	SCV000321365	pathogenic	not provided	2022-10-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced protein abundance, disruption of cellular trafficking, and inability to rescue plasma PPi and prevent ectopic mineralization (Saeidian et al., 2022); 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: 34205333, 16086317, 11427982, 11493310, 10811882, 17617515, 15894595, 28186352, 31589614, 34906475, 21603348)
Fulgent Genetics, Fulgent Genetics	RCV000762960	SCV000893398	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2	2024-04-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255802	SCV002234186	pathogenic	not provided	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1138 of the ABCC6 protein (p.Arg1138Trp). This variant is present in population databases (rs28939701, gnomAD 0.02%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10811882, 16086317, 18157818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6571). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000255802	SCV003812973	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255802	SCV005199093	likely pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing
OMIM	RCV000006949	SCV000027145	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2001-08-01	no assertion criteria provided	literature only
PXE International	RCV000006949	SCV000589056	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2021-03-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532305	SCV004722769	pathogenic	ABCC6-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The ABCC6 c.3412C>T variant is predicted to result in the amino acid substitution p.Arg1138Trp. This variant has been reported in multiple individuals with autosomal recessive pseudoxanthoma elasticum (see for example, Ringpfeil et al. 2000. PubMed ID: 10811882; Miksch et al. 2005. PubMed ID: 16086317; Tables S1, Szeri et al. 2022. PubMed ID: 36317459) and in individuals with heritable ectopic mineralization disorders (Table S1, Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.