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

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Aug 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000256117.45

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]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321360	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 15, 2022)	germline	clinical testing	Citation Link,
SCV000700696	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (May 8, 2017)	germline	clinical testing	Citation Link,
SCV000780531	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Aug 1, 2024)	germline	clinical testing	Citation Link,
SCV001097502	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Dec 31, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001551237	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	31	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000321360.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Recent study (not peer reviewed) including 590 probands with PXE showed a 2.9-fold enrichment of this variant among individuals with PXE versus population controls and incomplete penetrance, whereby only a small portion of probands with the p.(R391G) variant were symptomatic, but showed similar disease severity as probands with bi-allelic pathogenic loss-of-function variants (Szeri et al., 2020); Located in exon 9, a region with high sequence homology with an expressed pseudogene ABCC6P1; however, variant is not present in this pseudogene, which excludes the possibility that the high population frequency of p.(R391G) is due to a sequencing artifact; Arg391 residue is part of the 4th intracellular loop at the cytoplasmic surface of the protein and was suggested to have intramolecular interactions with several other residues and might be involved in the conformational switch of the protein (Szeri et al., 2020; Issa et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15086542, 34440381, 32445016, 11702217, 28102862, 11536079, 16410789, 16086317, 24008425, 14631379, 16835894, 29722917, 17617515, 23485117, 28655553, 31398764, 32818659, 22209248, 29487417, 32039214, 34205333, 32873932, 26135620, 34426522, 32442430, 34148116, 33005041)

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

From Eurofins Ntd Llc (ga), SCV000700696.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	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		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000780531.32

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	31	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		31	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001097502.2

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

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551237.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ABCC6 p.Arg391Gly variant was identified in 10 of 852 proband chromosomes (frequency: 0.0117) from individuals with Pseudoxanthoma Elasticum (PXE) and Generalized Arterial Calcification of Infancy (GACI) (Nitschke_2012_PMID: 22209248; Chassaing_2004_PMID: 15086542; Pfendner_2007_PMID:17617515; Schulz_2006_PMID: 16835894; Miksch_2006_PMID:168358954). The R391G variant was also identified in 3 of 7 families affected with PXE, found in the compound heterozygous state. In two of these families the clinical manifestation of PXE was less severe, and one individual was asymptomatic but may not have presented with disease yet (Ringpfeil_2006_PMID:16410789). Therefore the R391G may contribute to a less severe form of the disorder. The variant was also identified in dbSNP (ID: rs72653762), LOVD 3.0 and ClinVar (classified as pathogenic by GeneDx and PXE International and as a VUS by EGL Genetics, Laboratory for Molecular Medicine, CeGaT Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 1545 of 282338 chromosomes (5 homozygous) at a frequency of 0.005472 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was observed in the following populations: European (non-Finnish) in 1021 of 128772 chromosomes (freq: 0.007929), South Asian in 235 of 30614 chromosomes (freq: 0.007676), Other in 44 of 7218 chromosomes (freq: 0.006096), European (Finnish) in 95 of 25122 chromosomes (freq: 0.003782), Latino in 108 of 35440 chromosomes (freq: 0.003047), African in 40 of 24870 chromosomes (freq: 0.001608) and Ashkenazi Jewish in 2 of 10358 chromosomes (freq: 0.000193), while the variant was not observed in the East Asian population. The p.Arg391 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

Last Updated: Apr 20, 2025

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