Submissions for variant NM_001171.6(ABCC6):c.196dup (p.Ser66fs)

dbSNP: rs1064793538

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486589	SCV000566365	pathogenic	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34205333, 35387434, 25615550)
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783791	SCV005397369	pathogenic	Pseudoxanthoma elasticum, forme fruste	2022-03-14	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide duplication (dupT) that creates a premature termition codon in exon 2 of 31 of the ABCC6 gene 35 codons downstream of a frameshift introduced at codon 66. This variant is expected to generate a non-functiol allele through the expression of a truncated protein or a loss of ABCC6 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar) that has been observed in several compound heterozygous individuals affected by pseudoxanthoma elasticum (PMID: 34205333, 32270475, 25615550). This variant is absent from control population datasets (gnomAD database, 0 of approximately 250,000 alleles). To our knowledge, the impact of this variant on ABCC6 expression or function has not been examined in the published literature. However, loss of function variants are known to be a common mechanism of disease for ABCC6 (PMID: 17617515). Based on this evidence, we consider this a pathogenic variant. ACMG Criteria: PM2, PM3, PVS1
Fulgent Genetics, Fulgent Genetics	RCV005018794	SCV005638682	pathogenic	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2	2024-04-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535498	SCV004723141	pathogenic	ABCC6-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The ABCC6 c.196dupT variant is predicted to result in a frameshift and premature protein termination (p.Ser66Phefs*35). This variant was reported in individuals with pseudoxanthoma elasticum (Jin et al 2015. PubMed ID: 25615550; Table S1, Boraldi et al. 2021. PubMed ID: 34205333). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic.