NM_025215.6(PUS1):c.717C>A (p.Tyr239Ter) AND Myopathy, lactic acidosis, and sideroblastic anemia 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 15, 2022
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:: RCV000454345.2

Allele description [Variation Report for NM_025215.6(PUS1):c.717C>A (p.Tyr239Ter)]

NM_025215.6(PUS1):c.717C>A (p.Tyr239Ter)

Gene:

PUS1:pseudouridine synthase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.33

Genomic location:

Preferred name:

NM_025215.6(PUS1):c.717C>A (p.Tyr239Ter)

HGVS:

NC_000012.12:g.131941464C>A
NG_013039.1:g.17265C>A
NM_001002019.3:c.633C>A
NM_001002020.3:c.633C>A
NM_025215.6:c.717C>AMANE SELECT
NP_001002019.1:p.Tyr211Ter
NP_001002020.1:p.Tyr211Ter
NP_079491.2:p.Tyr239Ter
NC_000012.11:g.132426009C>A
NM_001002020.2:c.633C>A

Protein change:

Y211*

Links:

dbSNP: rs779651314

NCBI 1000 Genomes Browser:

rs779651314

Molecular consequence:

NM_001002019.3:c.633C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001002020.3:c.633C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_025215.6:c.717C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Myopathy, lactic acidosis, and sideroblastic anemia 1 (MLASA1)
Identifiers:: MONDO: MONDO:0024553; MedGen: C4551958; Orphanet: 2598; OMIM: 600462

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000538058	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 26, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004207197	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 15, 2022)	unknown	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

SCV000538058

Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 26, 2015)

germline

clinical testing

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

SCV004207197

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 15, 2022)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Details of each submission

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538058.1

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

Description

The c.633C>A (p.Tyr211ter) novel nonsense variant in the PUS1 gene is predicted to cause a premature protein truncation that lacks 188 amino acids (NP_001002020) in the C-terminal region of the protein. The C-terminal portion, which is predicted to be deleted as a result of this variant, comprises three helices that are necessary to maintain structural integrity and stability (Czudnochowski N et al., 2013). Indeed, a mutant form of hPus1 that lacks the important three helical domains in the C-terminal end was unable to solubilize (Czudnochowski N et al., 2013). Furthermore, Fernandez-Vizarra E et al. (2007) reported that two brothers who were affected with MLASA carried a homozygous variant (p.Glu192ter) that was also predicted to ablate the three C-terminal helices of the protein. This locus is conserved across species. The frequency of this variant is either absent or very low in the population databases (1000 Genome, Exome Sequencing Project and ExAC)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004207197.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 30, 2023

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