NM_001171.6(ABCC6):c.3904G>A (p.Gly1302Arg) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 31, 2024
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:: RCV000255838.13

Allele description [Variation Report for NM_001171.6(ABCC6):c.3904G>A (p.Gly1302Arg)]

NM_001171.6(ABCC6):c.3904G>A (p.Gly1302Arg)

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.3904G>A (p.Gly1302Arg)

HGVS:

NC_000016.10:g.16155010C>T
NG_007558.3:g.73608G>A
NM_001171.6:c.3904G>AMANE SELECT
NM_001351800.1:c.3562G>A
NP_001162.4:p.Gly1302Arg
NP_001162.5:p.Gly1302Arg
NP_001338729.1:p.Gly1188Arg
LRG_1115t1:c.3904G>A
LRG_1115:g.73608G>A
LRG_1115p1:p.Gly1302Arg
NC_000016.9:g.16248867C>T
NG_007558.2:g.73462G>A
NM_001171.5:c.3904G>A
NR_147784.1:n.3566G>A
O95255:p.Gly1302Arg

Protein change:

G1188R; GLY1302ARG

Links:

UniProtKB: O95255#VAR_013386; OMIM: 603234.0020; dbSNP: rs63749856

NCBI 1000 Genomes Browser:

rs63749856

Molecular consequence:

NM_001171.6:c.3904G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351800.1:c.3562G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147784.1:n.3566G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321368	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 31, 2024)	germline	clinical testing	Citation Link,
SCV002023918	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002204985	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11536079, 16086317, 21179111, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321368

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 31, 2024)

germline

clinical testing

Citation Link,

SCV002023918

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 15, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002204985

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.

Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Göring HH, Johnson EW, De Paepe A, Pope FM, Pasquali-Ronchetti I, Bercovitch L, Marais AS, Viljoen DL, Terry SF, Boyd CD.

Am J Hum Genet. 2001 Oct;69(4):749-64. Epub 2001 Aug 31. Erratum in: Am J Hum Genet 2001 Dec;69(6):1413. Am J Hum Genet 2002 Aug;71(2):448.

PubMed [citation]

PMID:: 11536079
PMCID:: PMC1226061

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000321368.11

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

Description

Published functional studies demonstrate that this variant, located at a position within an ATP binding region of the ABC transporter 2 domain, disrupts the ABCC6-mediated transport of glutathione conjugates (PMID: 11880368); 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: 19133228, 19339160, 16086317, 12673275, 17617515, 32873932, 17251343, 20189652, 32413269, 21179111, 11880368, 29480367, 15727254, 34205333, 11536079, 34906475)

#	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 Revvity Omics, Revvity, SCV002023918.3

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002204985.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1302 of the ABCC6 protein (p.Gly1302Arg). This variant is present in population databases (rs63749856, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 11536079, 16086317, 21179111). ClinVar contains an entry for this variant (Variation ID: 6579). 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%. For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 13, 2024

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