ClinVar Miner

Submissions for variant NM_001171.6(ABCC6):c.3490C>T (p.Arg1164Ter)

gnomAD frequency: 0.00012  dbSNP: rs72653744
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000006950 SCV000271307 pathogenic Autosomal recessive inherited pseudoxanthoma elasticum 2015-03-11 criteria provided, single submitter clinical testing The p.Arg1164X variant in ABCC6 has been previously reported in the homozygous s tate in one family with Pseudoxanthoma Elasticum (PXE; Struk 2000) and in 2 hete rozygous individuals with PXE in which another variant was not identified (Melon i 2001, Chassaing 2004). This variant has also been identified in 0.05% (4/8652 ) East Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadi nstitute.org/; dbSNP rs72653744). Although this variant has been seen in the gen eral population, its frequency is low enough to be consistent with a recessive c arrier frequency. This nonsense variant leads to a premature termination codon a t position 1164, which is predicted to lead to a truncated or absent protein. Co mplete loss of ABCC6 function is an established disease mechanism for PXE. In su mmary, this variant meets our criteria to be classified as pathogenic for PXE in an autosomal recessive manner (www.partners.org/personalizedmedicine/lmm).
GeneDx RCV000255402 SCV000321367 pathogenic not provided 2023-05-09 criteria provided, single submitter clinical testing Reported in the heterozygous state in three patients with pseudoxanthoma elasticum from two families, although a second ABCC6 variant was not identified in these cases (Meloni et al., 2001; Chassaing et al., 2004); Nonsense 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; This variant is associated with the following publications: (PMID: 1179012, 25525159, 28696355, 34205333, 34906475, 33879512, 31980526, 17617515, 11179012, 30056620, 29948180, 31269855, 30879837, 15086542, 28186352, 11439001, 10954200, 29480367, 31589614, 31345219)
Fulgent Genetics, Fulgent Genetics RCV001536083 SCV001752784 pathogenic Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2 2021-06-30 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000255402 SCV002018595 pathogenic not provided 2023-12-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000255402 SCV002137652 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1164*) 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 (rs72653744, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with pseudoxanthoma elasticum (PMID: 11179012, 11439001). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6572). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251887 SCV002523995 pathogenic See cases 2021-09-03 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1, PS4, PM2, PM3
OMIM RCV000006950 SCV000027146 pathogenic Autosomal recessive inherited pseudoxanthoma elasticum 2001-03-01 no assertion criteria provided literature only
PXE International RCV000006950 SCV000589062 pathogenic Autosomal recessive inherited pseudoxanthoma elasticum 2021-03-01 no assertion criteria provided research

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