ClinVar Miner

Submissions for variant NM_001171.6(ABCC6):c.1108A>G (p.Asn370Asp)

gnomAD frequency: 0.00030  dbSNP: rs72653760
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198805 SCV001369800 uncertain significance Arterial calcification, generalized, of infancy, 2 2018-10-22 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP5,BP4.
PreventionGenetics, part of Exact Sciences RCV004535566 SCV004116735 likely pathogenic ABCC6-related disorder 2023-07-27 criteria provided, single submitter clinical testing The ABCC6 c.1108A>G variant is predicted to result in the amino acid substitution p.Asn370Asp. This variant has been reported in the compound heterozygous state in multiple individuals with pseudoxanthoma elasticum. In at least three patients, the second variant affecting the ABCC6 gene was the c.3421C>T (p.Arg1141Ter) recurrent pathogenic variant (Miksch et al. 2005. PubMed ID: 16086317, Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16295926-T-C). This variant is interpreted as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017652 SCV004847977 uncertain significance not provided 2016-11-11 criteria provided, single submitter clinical testing The p.Asn370Asp variant in ABCC6 has been reported in 2 compound heterozygous individuals with Pseudoxanthoma elasticum (Miksch 2005). This variant has been identified in 0.038% (25/66650) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72653760). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. However, computational prediction tools do not provide strong support for an impact to the protein and the amino acid position is poorly conserved reducing confidence in a pathogenic interpretation. In summary, additional studies are required to establish the clinical significance of the p.Asn370Asp variant given limited cases studies and conflicting computational and conservation assessments. It should also be noted that this variant occurs in a region of the gene that has high homology to a pseudogene. Caution should be exercised in the analytical detection of the variant in patient DNA.
PXE International RCV000499173 SCV000588947 uncertain significance Autosomal recessive inherited pseudoxanthoma elasticum 2021-03-01 no assertion criteria provided research

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