NM_001171.6(ABCC6):c.4016G>A (p.Arg1339His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 12, 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:: RCV000255253.6

Allele description [Variation Report for NM_001171.6(ABCC6):c.4016G>A (p.Arg1339His)]

NM_001171.6(ABCC6):c.4016G>A (p.Arg1339His)

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.4016G>A (p.Arg1339His)

HGVS:

NC_000016.10:g.16154898C>T
NG_007558.3:g.73720G>A
NM_001171.6:c.4016G>AMANE SELECT
NM_001351800.1:c.3674G>A
NP_001162.4:p.Arg1339His
NP_001162.5:p.Arg1339His
NP_001338729.1:p.Arg1225His
LRG_1115t1:c.4016G>A
LRG_1115:g.73720G>A
LRG_1115p1:p.Arg1339His
NC_000016.9:g.16248755C>T
NG_007558.2:g.73574G>A
NM_001171.5:c.4016G>A
NR_147784.1:n.3678G>A
O95255:p.Arg1339His

Protein change:

R1225H

Links:

UniProtKB: O95255#VAR_067904; dbSNP: rs63750622

NCBI 1000 Genomes Browser:

rs63750622

Molecular consequence:

NM_001171.6:c.4016G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351800.1:c.3674G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147784.1:n.3678G>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
SCV000321370	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Mar 4, 2016)	germline	clinical testing	Citation Link,
SCV002242901	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18157818, 16086317, 19339160, 27994049, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321370

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Mar 4, 2016)

germline

clinical testing

Citation Link,

SCV002242901

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (5)
[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

Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart.

Vanakker OM, Leroy BP, Coucke P, Bercovitch LG, Uitto J, Viljoen D, Terry SF, Van Acker P, Matthys D, Loeys B, De Paepe A.

Hum Mutat. 2008 Jan;29(1):205.

PubMed [citation]

PMID:: 18157818

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

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000321370.6

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

Description

The R1339H variant in the ABCC6 gene has been reported at least seven times previously in association with PXE (Miksch et al., 2005, Pfendner et al. 2007, Vanakker et al., 2008). The R1339H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1339H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species In silico analysis predicts this variant is probably damaging to the protein structure/function as it occurs in the highly conserved second ATP binding domain required for proper gene function and in which numerous pathogenic variants are clustered. Missense variants at the same residue (R1339C, R1339L) and in nearby residues (L1335P, L1335Q, I1342T) have been reported in the Human Gene Mutation Database in association with PXE (Stenson et al., 2014), supporting the functional importance of this region of the protein. According to the ACMG Guidelines this variant is classified as likely pathogenic; however, the unlikely possibility that it is benign cannot be excluded.

#	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 Invitae, SCV002242901.3

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1339 of the ABCC6 protein (p.Arg1339His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 16086317, 18157818). This variant is also known as p.R1339Q. ClinVar contains an entry for this variant (Variation ID: 265021). 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%. This variant disrupts the p.Arg1339 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16086317, 19339160, 27994049). 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: Feb 20, 2024

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