rs63751215
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_001171.6(ABCC6):c.3661C>T(p.Arg1221Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1221H) has been classified as Pathogenic.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.3661C>T | p.Arg1221Cys | missense_variant | 26/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.3319C>T | p.Arg1107Cys | missense_variant | 26/31 | ||
ABCC6 | NR_147784.1 | n.3323C>T | non_coding_transcript_exon_variant | 24/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.3661C>T | p.Arg1221Cys | missense_variant | 26/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.3661C>T | p.Arg1221Cys | missense_variant, NMD_transcript_variant | 26/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.*670C>T | 3_prime_UTR_variant, NMD_transcript_variant | 24/29 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251368Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135882
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461862Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727234
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74284
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 16086317, 25062064, 15727254, 16854481, 17617515, 15645653, 12673275) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1221 of the ABCC6 protein (p.Arg1221Cys). This variant is present in population databases (rs63751215, gnomAD 0.006%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 12673275, 15645653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 433319). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC6 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Pathogenic, no assertion criteria provided | research | PXE International | Mar 01, 2021 | - - |
ABCC6-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2023 | The ABCC6 c.3661C>T variant is predicted to result in the amino acid substitution p.Arg1221Cys. This variant has been reported in the compound heterozygous state in individuals with pseudoxanthoma elasticum (PX) ( Hu et al. 2003. PubMed ID: 12673275; Hu et al. 2004. PubMed ID: 15727254; Miksch et al. 2005. PubMed ID: 16086317; Pfender et al. 2007. PubMed ID: 17617515). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16253413-G-A). In addition, an alternate change affecting the same amino acid, (p.Arg1221His) has been reported in the compound heterozygous state with the ABCC6 p.1141* variant in an individual with PXE (Kiec-Wilk et al. 2007. PubMed ID: 16854481), in the homozygous state in an individual with generalized calcification of infancy (GACI) (Nitschke et al. 2012. PubMed ID: 22209248), and has been reported as a pathogenic secondary (carrier) finding in an exome cohort (Capalbo et al. 2019. PubMed ID: 31589614). The c.3661C>T (p.Arg1221Cys) variant is interpreted as pathogenic. - |
Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at