NM_001171.6(ABCC6):c.2858T>A (p.Leu953His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 5, 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:: RCV001857044.9

Allele description [Variation Report for NM_001171.6(ABCC6):c.2858T>A (p.Leu953His)]

NM_001171.6(ABCC6):c.2858T>A (p.Leu953His)

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.2858T>A (p.Leu953His)

HGVS:

NC_000016.10:g.16169783A>T
NG_007558.3:g.58835T>A
NM_001171.6:c.2858T>AMANE SELECT
NM_001351800.1:c.2516T>A
NP_001162.4:p.Leu953His
NP_001162.5:p.Leu953His
NP_001338729.1:p.Leu839His
LRG_1115t1:c.2858T>A
LRG_1115:g.58835T>A
LRG_1115p1:p.Leu953His
NC_000016.9:g.16263640A>T
NG_007558.2:g.58689T>A
NM_001171.5:c.2858T>A
NR_147784.1:n.2720T>A

Protein change:

L839H

Links:

dbSNP: rs72657700

NCBI 1000 Genomes Browser:

rs72657700

Molecular consequence:

NM_001171.6:c.2858T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351800.1:c.2516T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_147784.1:n.2720T>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
SCV002182613	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11536079, 34906475, 28492532
SCV003824354	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002182613

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 5, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003824354

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 24, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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

Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.

Saeidian AH, Youssefian L, Huang J, Touati A, Vahidnezhad H, Kowal L, Caffet M, Wurst T, Singh J, Snook AE, Ryu E, Fortina P, Terry SF, Schoenecker JG, Uitto J, Li Q.

Genet Med. 2022 Jan;24(1):75-86. doi: 10.1016/j.gim.2021.08.011. Epub 2021 Nov 30.

PubMed [citation]

PMID:: 34906475
PMCID:: PMC8943706

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002182613.4

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 953 of the ABCC6 protein (p.Leu953His). This variant is present in population databases (rs72657700, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of pseudoxanthoma elasticum (PMID: 11536079, 34906475). ClinVar contains an entry for this variant (Variation ID: 433297). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Revvity Omics, Revvity, SCV003824354.2

#	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

Last Updated: Sep 29, 2024

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