NM_139119.3(YY1AP1):c.412-1G>A AND Grange syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 20, 2020
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:: RCV000714980.8

Allele description [Variation Report for NM_139119.3(YY1AP1):c.412-1G>A]

NM_139119.3(YY1AP1):c.412-1G>A

Gene:

YY1AP1:YY1 associated protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q22

Genomic location:

Preferred name:

NM_139119.3(YY1AP1):c.412-1G>A

HGVS:

NC_000001.11:g.155672732C>T
NM_001198899.2:c.379-1G>A
NM_001198900.2:c.379-1G>A
NM_001198901.2:c.412-1G>A
NM_001198902.2:c.412-1G>A
NM_001198903.1:c.826-1G>A
NM_001198904.1:c.826-1G>A
NM_001198905.2:c.412-1G>A
NM_001198906.2:c.610-1G>A
NM_018253.4:c.379-1G>A
NM_139118.3:c.610-1G>A
NM_139119.3:c.412-1G>AMANE SELECT
NM_139121.3:c.214-1G>A
NC_000001.10:g.155642523C>T

Nucleotide change:

IVS5AS, G-A, -4

Links:

OMIM: 607860.0006; dbSNP: rs199653824

NCBI 1000 Genomes Browser:

rs199653824

Molecular consequence:

NM_001198899.2:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198900.2:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198901.2:c.412-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198902.2:c.412-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198903.1:c.826-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198904.1:c.826-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198905.2:c.412-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001198906.2:c.610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_018253.4:c.379-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_139118.3:c.610-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_139119.3:c.412-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_139121.3:c.214-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

effect on RNA splicing [Variation Ontology: 0362]

Observations:

Condition(s)

Name:: Grange syndrome (GRNG)
Synonyms:: GRANGE OCCLUSIVE ARTERIAL SYNDROME
Identifiers:: MONDO: MONDO:0011243; MedGen: C1865267; Orphanet: 79094; OMIM: 602531

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000747037	Institute of Human Genetics Greifswald, Research Division, University Medicine Greifswald	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 2, 2018)	not applicable	in vitro	PubMed (1) [See all records that cite this PMID]
SCV001370538	OMIM	no assertion criteria provided	Pathogenic (Jul 2, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001430090	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jan 20, 2020)	maternal	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000747037

Institute of Human Genetics Greifswald, Research Division, University Medicine Greifswald

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 2, 2018)

not applicable

in vitro

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

SCV001370538

OMIM

no assertion criteria provided

Pathogenic
(Jul 2, 2020)

germline

literature only

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

SCV001430090

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Pathogenic
(Jan 20, 2020)

maternal

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing.

Rath M, Spiegler S, Strom TM, Trenkler J, Kroisel PM, Felbor U.

Am J Med Genet A. 2019 Feb;179(2):295-299. doi: 10.1002/ajmg.a.60700. Epub 2018 Dec 17.

PubMed [citation]

PMID:: 30556293
PMCID:: PMC6590215

Details of each submission

From Institute of Human Genetics Greifswald, Research Division, University Medicine Greifswald, SCV000747037.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	PubMed (1)

Description

RT-PCR on RNA from blood lymphocytes confirmed skipping of exon 6 which causes a frameshift.

Description

The c.826-1G>A variant in YY1AP1 has been identified in a compound heterozygous state with another YY1AP1 splice mutation. Additionally, RT-PCR on RNA from blood lymphocytes confirmed skipping of exon 6 which causes a frameshift. In summary, the c.826-1G>A variant meets the ACMG criteria to be classified as pathogenic based upon segregation studies, population frequency data and functional evidence.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	RNA from blood lymphocytes	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV001370538.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 sibs with Grange syndrome (GRNG; 602531), Rath et al. (2019) identified compound heterozygous mutations in the YY1AP1 gene: IVS5-4G-A (c.826-1G-A), inherited from the father, and IVS6+23T-G (c.977+23T-G, 607860.0007), inherited from the mother. The mutations were identified by sequencing of near-splice regions and Sanger sequencing, following failure of whole-exome sequencing to identify a candidate gene. A younger sib, aged 12 years, was heterozygous for the maternal mutation. The mutation in intron 5 was predicted to cause skipping of exon 6. The mutation in intron 6 was predicted to create a novel donor splice site in intron 6, resulting in a frameshift due to exonization of 22 intronic nucleotides (Ala333GlyfsTer10). The variants were classified as loss-of-function mutations and as pathogenic according to ACMG guidelines. The splice site defects were confirmed by RT-PCR in all 4 sibs and the carrier parents. The parents were asymptomatic and had no stenoocclusive lesions, and the 12-year-old sib had as yet no vascular lesions. The c.977+23T-G variant was not present in the gnomAD database, whereas the c.826-1G-A variant was present in 3 heterozygotes. Functional studies were not performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001430090.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	1	blood	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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