NM_001171.6(ABCC6):c.2855TCCTCT[1] (p.952FL[1]) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 22, 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:: RCV000255723.6

Allele description [Variation Report for NM_001171.6(ABCC6):c.2855TCCTCT[1] (p.952FL[1])]

NM_001171.6(ABCC6):c.2855TCCTCT[1] (p.952FL[1])

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

16p13.11

Genomic location:

Preferred name:

NM_001171.6(ABCC6):c.2855TCCTCT[1] (p.952FL[1])

Other names:

ABCC6_00414;c.2861_2866del6

HGVS:

NC_000016.10:g.16169779GAAGAG[1]
NG_007558.3:g.58832TCCTCT[1]
NM_001171.6:c.2855TCCTCT[1]MANE SELECT
NM_001351800.1:c.2513TCCTCT[1]
NP_001162.5:p.952FL[1]
NP_001338729.1:p.838FL[1]
LRG_1115t1:c.2855TCCTCT[1]
LRG_1115:g.58832TCCTCT[1]
LRG_1115p1:p.952FL[1]
NC_000016.9:g.16263632_16263637del
NC_000016.9:g.16263636GAAGAG[1]
NG_007558.2:g.58686TCCTCT[1]
NM_001171.5:c.2861_2866delTCCTCT
NR_147784.1:n.2717TCCTCT[1]

Links:

dbSNP: rs767359198

NCBI 1000 Genomes Browser:

rs767359198

Molecular consequence:

NM_001171.6:c.2855TCCTCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001351800.1:c.2513TCCTCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NR_147784.1:n.2717TCCTCT[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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ubiquitin domain-containing protein UBFD1 [Homo sapiens]
ubiquitin domain-containing protein UBFD1 [Homo sapiens]
gi|77917604|ref|NP_061989.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321362	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Mar 23, 2018)	germline	clinical testing	Citation Link,
SCV002193823	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25264593, 33005041, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321362

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Mar 23, 2018)

germline

clinical testing

Citation Link,

SCV002193823

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 22, 2023)

germline

clinical testing

PubMed (3)
[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

Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.

Hosen MJ, Van Nieuwerburgh F, Steyaert W, Deforce D, Martin L, Leftheriotis G, De Paepe A, Coucke PJ, Vanakker OM.

J Invest Dermatol. 2015 Apr;135(4):992-998. doi: 10.1038/jid.2014.421. Epub 2014 Sep 29.

PubMed [citation]

PMID:: 25264593
PMCID:: PMC4378258

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

Ferreira CR, Hackbarth ME, Ziegler SG, Pan KS, Roberts MS, Rosing DR, Whelpley MS, Bryant JC, Macnamara EF, Wang S, Müller K, Hartley IR, Chew EY, Corden TE, Jacobsen CM, Holm IA, Rutsch F, Dikoglu E, Chen MY, Mughal MZ, Levine MA, Gafni RI, et al.

Genet Med. 2021 Feb;23(2):396-407. doi: 10.1038/s41436-020-00983-0. Epub 2020 Oct 2.

PubMed [citation]

PMID:: 33005041
PMCID:: PMC7867608

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000321362.7

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

Description

The c.2861_2866delTCCTCT variant has been published previously in three patients who were also heterozygous for the R518Q variant in the ABCC6 gene (Hosen et al., 2015). It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This deletion causes the loss of two conserved residues, Phenylalanine 954 and Leucine 955, in a conserved transmembrane domain. In summary, the c.2861_2866delTCCTCT variant is a strong candidate for a disease-causing variant.

#	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, SCV002193823.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 265019). This variant has been observed in individual(s) with pseudoxanthoma elasticum or generalized arterial calcification of infancy (PMID: 25264593, 33005041). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs767359198, gnomAD 0.02%). This variant, c.2861_2866del, results in the deletion of 2 amino acid(s) of the ABCC6 protein (p.Phe954_Leu955del), but otherwise preserves the integrity of the reading frame.

#	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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