Submissions for variant NM_001171.6(ABCC6):c.1552C>T (p.Arg518Ter)

gnomAD frequency: 0.00004  dbSNP: rs72650700

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191057	SCV000245446	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste	2014-04-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in a 39-year-old male with hereditary anemia, angioid streaks on retina, possible pseudoxanthoma elasticum, fatigue, chronic joint pain. Variant was in trans with a common missense variant [c.793A>G (p.R265G)].
GeneDx	RCV000429924	SCV000516089	pathogenic	not provided	2018-07-09	criteria provided, single submitter	clinical testing	The p.R518X nonsense variant in the ABCC6 gene has been reported previously in association with PXE (Meloni et al., 2001). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret this variant as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000023279	SCV001366804	pathogenic	Arterial calcification, generalized, of infancy, 2	2019-08-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
CeGaT Center for Human Genetics Tuebingen	RCV000429924	SCV001747147	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000429924	SCV002245561	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg518*) in the ABCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is present in population databases (rs72650700, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 11439001). ClinVar contains an entry for this variant (Variation ID: 30339). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000023280	SCV002573157	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000030339/ PMID: 11439001). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002477007	SCV002793157	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2	2022-03-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528132	SCV004109288	pathogenic	ABCC6-related disorder	2022-09-06	criteria provided, single submitter	clinical testing	The ABCC6 c.1552C>T variant is predicted to result in premature protein termination (p.Arg518*). This variant has been reported in an individual with autosomal recessive pseudoxanthoma elasticum (PXE) and autosomal recessive generalized calcification of infancy (GACI) (Table 1, Meloni et al. 2001. PubMed ID: 11439001; Table 1, Miksch et al. 2005. PubMed ID: 16086317; Table 2, Pfendner et al. 2007. PubMed ID: 17617515; Table 2, Nitschke et al. 2011. PubMed ID: 22209248; Table S1, Boraldi et al. 2021. PubMed ID: 34205333; Table S1, Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16284104-G-A). Nonsense variants in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000023279	SCV000044570	pathogenic	Arterial calcification, generalized, of infancy, 2	2012-01-13	no assertion criteria provided	literature only
OMIM	RCV000023280	SCV000044571	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum	2012-01-13	no assertion criteria provided	literature only
PXE International	RCV000023280	SCV000588966	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum		no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000023280	SCV000607215	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.