NM_173076.3(ABCA12):c.2296C>T (p.Gln766Ter) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 14, 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:: RCV000578837.2

Allele description [Variation Report for NM_173076.3(ABCA12):c.2296C>T (p.Gln766Ter)]

NM_173076.3(ABCA12):c.2296C>T (p.Gln766Ter)

Gene:

ABCA12:ATP binding cassette subfamily A member 12 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_173076.3(ABCA12):c.2296C>T (p.Gln766Ter)

HGVS:

NC_000002.12:g.215011475G>A
NG_007074.1:g.131953C>T
NM_015657.4:c.1342C>T
NM_173076.3:c.2296C>TMANE SELECT
NP_056472.2:p.Gln448Ter
NP_775099.2:p.Gln766Ter
NC_000002.11:g.215876199G>A
NM_173076.2:c.2296C>T
NR_103740.2:n.2738C>T

Protein change:

Q448*

Links:

dbSNP: rs772046102

NCBI 1000 Genomes Browser:

rs772046102

Molecular consequence:

NR_103740.2:n.2738C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_015657.4:c.1342C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_173076.3:c.2296C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000681109	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Nov 15, 2017)	germline	clinical testing	Citation Link,
SCV004482921	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20672373, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000681109

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Nov 15, 2017)

germline

clinical testing

Citation Link,

SCV004482921

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 14, 2023)

germline

clinical testing

PubMed (2)
[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

ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts.

Akiyama M.

Hum Mutat. 2010 Oct;31(10):1090-6. doi: 10.1002/humu.21326. Review.

PubMed [citation]

PMID:: 20672373

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000681109.2

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

Description

The Q766X variant in the ABCA12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q766X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Q766X as a likely pathogenic 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 Invitae, SCV004482921.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Gln766*) in the ABCA12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA12 are known to be pathogenic (PMID: 20672373). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ABCA12-related conditions. ClinVar contains an entry for this variant (Variation ID: 489123). 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 28, 2024

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