NM_001171.6(ABCC6):c.1171A>G (p.Arg391Gly) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 19, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000455861.7

Allele description [Variation Report for NM_001171.6(ABCC6):c.1171A>G (p.Arg391Gly)]

NM_001171.6(ABCC6):c.1171A>G (p.Arg391Gly)

Gene:

ABCC6:ATP binding cassette subfamily C member 6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.11

Genomic location:

Preferred name:

NM_001171.6(ABCC6):c.1171A>G (p.Arg391Gly)

HGVS:

NC_000016.10:g.16202006T>C
NG_007558.3:g.26612A>G
NM_001171.6:c.1171A>GMANE SELECT
NM_001351800.1:c.829A>G
NP_001162.4:p.Arg391Gly
NP_001162.5:p.Arg391Gly
NP_001338729.1:p.Arg277Gly
LRG_1115t1:c.1171A>G
LRG_1115:g.26612A>G
LRG_1115p1:p.Arg391Gly
NC_000016.9:g.16295863T>C
NG_007558.2:g.26466A>G
NM_001171.5:c.1171A>G
NR_147784.1:n.1208A>G
O95255:p.Arg391Gly

Protein change:

R277G

Links:

UniProtKB: O95255#VAR_067850; dbSNP: rs72653762

NCBI 1000 Genomes Browser:

rs72653762

Molecular consequence:

NM_001171.6:c.1171A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351800.1:c.829A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_147784.1:n.1208A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000538215	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 28, 2016)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16086317, 14631379, 16835894, 15086542, 22209248, 11536079, 17617515, 11702217, 16410789, 24033266
SCV003934758	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 19, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18513494, 15086542, 16410789, 16835894, 36317459 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000538215

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 28, 2016)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV003934758

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 19, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.

Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zäch S, Daugherty C, Ramesar RK, Lebwohl M, Hohl D, Neldner KH, Lindpaintner K, Richards RI, Struk B.

Hum Mutat. 2005 Sep;26(3):235-48.

PubMed [citation]

PMID:: 16086317

Assessment of a rapid-cycle PCR assay for the identification of the recurrent c.3421C>T mutation in the ABCC6 gene in pseudoxanthoma elasticum patients.

Götting C, Schulz V, Hendig D, Grundt A, Dreier J, Szliska C, Brinkmann T, Kleesiek K.

Lab Invest. 2004 Jan;84(1):122-30.

PubMed [citation]

PMID:: 14631379

See all PubMed Citations (12)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000538215.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in an individual with cutanous Pseudoxanthoma Elasticum who also had a multi exon deletion in ABCC6 (Chassing 2004). Also reported in two probands and in one affected twin sibling with generalized arterial calcification of infancy (Nitschke 2012), one of whom also had a frameshift variant. This was the only variant identified in the twins. MAF 0.8% with 3 homozygotes in ExAC.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934758.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: ABCC6 c.1171A>G (p.Arg391Gly) results in a non-conservative amino acid change to a well-conserved residue (HGMD) located in a helix at the cytoplasmic site of transmembrane domain 1 (Szeri_2022) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 250940 control chromosomes in the gnomAD database, including 5 homozygotes. c.1171A>G has been reported in the literature in many individuals affected with Pseudoxanthoma Elasticum who are compound heterozygous with other pathogenic variants (e.g. Chassaing_2004, Garcia-Fernandez_2008, Ringpfeil_2006, Saeidan_2022, Schulz_2006, Szeri_2002). A modest enrichment in the frequency of the variant in affected individuals over the general population suggests the possibility that it may be associated with disease with a low penetrance, possibly mediated by interactions with unidentified variants in an interacting partner protein of ABCC6 (Szeri_2022). These reports do not provide unequivocal conclusions about association of the variant with Pseudoxanthoma Elasticum. At least two publications report experimental evidence evaluating an impact on protein function, finding no damaging effect of this variant on expression, subcellular localization, or functional activity (Szeri_2022, Saeidan_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36317459, 15086542, 16410789, 16835894, 18513494, 16835894). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations, and classified it as likely benign (n=2), pathogenic (n=1), and uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2025

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