16-16163078-G-A

Variant names:

• chr16-16163078-G-A
• rs72653706
• NM_001171.6:c.3421C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001171.6(ABCC6):​c.3421C>T​(p.Arg1141*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,922 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: ABCC6 NM_001171.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:31
• Conservation: PhyloP100: 3.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-16163078-G-A is Pathogenic according to our data. Variant chr16-16163078-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16163078-G-A is described in Lovd as [Pathogenic]. Variant chr16-16163078-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3421C>T	p.Arg1141*	stop_gained	Exon 24 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3079C>T	p.Arg1027*	stop_gained	Exon 24 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.3169-1514C>T		intron_variant	Intron 22 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3421C>T	p.Arg1141*	stop_gained	Exon 24 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000622290.5	n.3421C>T		non_coding_transcript_exon_variant	Exon 24 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*516-1514C>T		intron_variant	Intron 22 of 28	2		ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00141 AC: 355 AN: 251296 Hom.: 0 AF XY: 0.00154 AC XY: 209 AN XY: 135858

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00166 AC: 2431 AN: 1461600 Hom.: 5 Cov.: 33 AF XY: 0.00171 AC XY: 1245 AN XY: 727076

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00282

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74490

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.00108

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00139 AC: 169

EpiCase AF: 0.00191

EpiControl AF: 0.00190

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:13

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCC6: PM3:Very Strong, PVS1, PP1:Strong, PM2:Supporting, PS3:Supporting -

Mar 02, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Expression studies of the R1141X variant in leukocytes and cultured fibroblasts from affected individuals homozygous for R1141X demonstrate mRNA instability and absence of the protein in immunohistochemistry studies (Hu et al., 2003); Early speculation that heterozygosity for R1141X may increase the risk of coronary artery disease has not been confirmed in a large cohort study (Trip et al., 2002; Hornstrup et al., 2011).; This variant is associated with the following publications: (PMID: 29800625, 29709427, 31646622, 32646269, 22209248, 12176944, 19929409, 10835643, 25525159, 24352041, 12714611, 23746223, 27133371, 10811882, 23675997, 16086317, 21831958, 26982014, 16854481, 16384891, 16133423, 14631379, 24008425, 28102862, 18800149, 12384774, 30206659, 29722917, 30985656, 31980526, 34440381, 33812167, 34426522, 31589614, 33726816) -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1141*) 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 (rs72653706, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 10835642, 12714611, 17617515, 22209248, 26982014). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6559). 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. -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:10

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 25, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 17, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with generalized infantile arterial calcification 2 (MIM#614473), pseudoxanthoma elasticum (MIM#264800) and forme fruste pseudoxanthoma elasticum (MIM#177850). (I) 0106 - This gene is associated with autosomal recessive disease. OIder publications suggest dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability with age-dependent severity has been well reported (PMID: 28102862). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (396 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many of these variants have been reported times as pathogenic, and are reported in many individuals with pseudoxanthoma elasticum or generalized arterial calcification (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, in both homozygous or compound heterozygous individuals with pseudoxanthoma elasticum or generalized arterial calcification of infancy. It represents one of the most common variants within Caucasian populations (ClinVar, PMID: 28102862). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 13, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

PXE International

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 04, 2023

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is predicted to cause a premature termination of the protein and the resultant protein will probably lack part of the ABC transmembrane type-1 domain and the entire ABC transporter 2 domain of the protein [UniProt]; this will likely result in loss-of-function. Due to the introduction of a premature stop codon, this aberrant transcript will likely be targeted by the nonsense-mediated mRNA decay (NMD) mechanism [PMID: 15040442]. The identified variant was previously reported in individuals with pseudoxanthoma elasticum and observed to segregate with disease in related individuals [PMID: 10835642, 12714611, 17617515, 22209248, 26982014]. Loss-of-function variants in ABCC6 are known to be pathogenic [PMID: 11536079, 17617515]. -

Sep 04, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM3_STR,PP4; Identified as compund heterozygous with NM_001171.6:c.3413G>A -

Mar 09, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2024

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arterial calcification, generalized, of infancy, 2 Pathogenic:3

Jan 13, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. This variant was detected in homozygous state. -

Jun 30, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCC6-related disorder Pathogenic:2

Sep 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCC6 c.3421C>T variant is predicted to result in premature protein termination (p.Arg1141*). This variant has been reported to be causative for autosomal recessive pseudoxanthoma elasticum (PXE) (Ringpfeil et al. 2000. PubMed ID: 10811882, ABCC6 gene was reported as MRP6 gene; Hu et al. 2003. PubMed ID: 12714611; Miksch et al. 2005. PubMed ID: 16086317). In addition, several studies have reported a significantly increased risk of coronary artery disease in carriers of the ABCC6 p.Arg1141* variant (Trip et al. 2002. PubMed ID: 12176944; Köblös et al. 2010. PubMed ID: 19929409). Nonsense variants in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Aug 30, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM3_Strong -

Cutis laxa;C0332563:Papule Pathogenic:1

Oct 24, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Apr 05, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS3, PM3 -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.89
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs72653706; hg19: chr16-16256935;