rs63750427

Positions:

• chr16-16163158-C-G
• chr16-16163158-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001171.6(ABCC6):​c.3341G>C​(p.Arg1114Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,461,368 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1114C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.12

Genes affected

ABCC6 (HGNC:57): (ATP binding cassette subfamily C member 6) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]

ABCC6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 70) in uniprot entity MRP6_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16163159-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 16-16163158-C-G is Pathogenic according to our data. Variant chr16-16163158-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 6562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16163158-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3341G>C	p.Arg1114Pro	missense_variant	24/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.2999G>C	p.Arg1000Pro	missense_variant	24/31		NP_001338729.1
ABCC6	NR_147784.1	n.3169-1594G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3341G>C	p.Arg1114Pro	missense_variant	24/31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000622290.5	n.3341G>C		non_coding_transcript_exon_variant	24/32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*516-1594G>C		intron_variant		2		ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250814 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461368 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 726972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000220 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2

Pathogenic, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2018	- -

ABCC6-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2022

The ABCC6 c.3341G>C variant is predicted to result in the amino acid substitution p.Arg1114Pro. This variant was reported in individuals with pseudoxanthoma elasticum (Le Saux et al. 2000. PubMed ID: 10835642; Le Saux et al. 2001. PubMed ID: 11536079; Hu et al. 2003. PubMed ID: 12850230). Of note, other variants impacting this same amino acid have been reported in individuals with pseudoxanthoma elasticum [c.3340C>T (p.Arg1114Cys) and c.3341G>A (p.Arg1114His)] (Gheduzzi et al. 2004. PubMed ID: 15459974; Supplementary Table S2, Verschuere et al. 2020. PubMed ID: 32873932; Supplementary Table S1, Boraldi et al. 2021. PubMed ID: 34205333). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16257015-C-G). Taken together, this variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1114 of the ABCC6 protein (p.Arg1114Pro). This variant is present in population databases (rs63750427, gnomAD 0.007%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10835642, 17724214). ClinVar contains an entry for this variant (Variation ID: 6562). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 24352041). This variant disrupts the p.Arg1114 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16835894, 18157818, 18513494). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Gain of glycosylation at R1114 (P = 0.0567);
MVP		0.98
MPC		0.48
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63750427; hg19: chr16-16257015;