NM_001171.6(ABCC6):c.3940C>T (p.Arg1314Trp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 30, 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:: RCV000254915.9

Allele description [Variation Report for NM_001171.6(ABCC6):c.3940C>T (p.Arg1314Trp)]

NM_001171.6(ABCC6):c.3940C>T (p.Arg1314Trp)

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.3940C>T (p.Arg1314Trp)

HGVS:

NC_000016.10:g.16154974G>A
NG_007558.3:g.73644C>T
NM_001171.6:c.3940C>TMANE SELECT
NM_001351800.1:c.3598C>T
NP_001162.4:p.Arg1314Trp
NP_001162.5:p.Arg1314Trp
NP_001338729.1:p.Arg1200Trp
LRG_1115t1:c.3940C>T
LRG_1115:g.73644C>T
LRG_1115p1:p.Arg1314Trp
NC_000016.9:g.16248831G>A
NG_007558.2:g.73498C>T
NM_001171.5:c.3940C>T
NR_147784.1:n.3602C>T
O95255:p.Arg1314Trp

Protein change:

R1200W; ARG1314TRP

Links:

UniProtKB: O95255#VAR_011495; OMIM: 603234.0006; dbSNP: rs63750759

NCBI 1000 Genomes Browser:

rs63750759

Molecular consequence:

NM_001171.6:c.3940C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351800.1:c.3598C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_147784.1:n.3602C>T - 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
SCV000321369	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 26, 2022)	germline	clinical testing	Citation Link,
SCV001587439	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10835642, 16835894, 19339160, 30537162, 21935449, 23483032, 27994049, 29722917, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321369

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 26, 2022)

germline

clinical testing

Citation Link,

SCV001587439

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (9)
[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

Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.

Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali-Ronchetti I, Pope FM, Richards A, Terry S, Bercovitch L, de Paepe A, Boyd CD.

Nat Genet. 2000 Jun;25(2):223-7.

PubMed [citation]

PMID:: 10835642

Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).

Schulz V, Hendig D, Henjakovic M, Szliska C, Kleesiek K, Götting C.

Hum Mutat. 2006 Aug;27(8):831.

PubMed [citation]

PMID:: 16835894

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000321369.8

#	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 a damaging effect with R1314W resulting in abnormal protein trafficking and inappropriate intracellular accumulation (Le Saux et al., 2011); 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: 16392638, 22209248, 10835642, 30537162, 34205333, 34906475, 21935449, 24008425, 19339160, 24352041, 23483032, 27994049, 28102862, 28416300, 27826008, 32445016, 31589614, 34440381, 33005041, 32873932)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001587439.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1314 of the ABCC6 protein (p.Arg1314Trp). This variant is present in population databases (rs63750759, gnomAD 0.3%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10835642, 16835894, 19339160, 30537162). ClinVar contains an entry for this variant (Variation ID: 6564). 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: 21935449, 23483032, 27994049). This variant disrupts the p.Arg1314 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29722917). 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.

#	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: Sep 29, 2024

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