NM_031307.4(PUS3):c.-47+3170T>C AND Hydrolethalus syndrome 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 15, 2021
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:: RCV000454127.10

Allele description [Variation Report for NM_031307.4(PUS3):c.-47+3170T>C]

NM_031307.4(PUS3):c.-47+3170T>C

Genes:

HYLS1:HYLS1 centriolar and ciliogenesis associated [Gene - OMIM - HGNC]
PUS3:pseudouridine synthase 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q24.2

Genomic location:

Preferred name:

NM_031307.4(PUS3):c.-47+3170T>C

HGVS:

NC_000011.10:g.125900000A>G
NG_011842.1:g.21387A>G
NG_033067.1:g.8222T>C
NG_033067.2:g.8206T>C
NM_001134793.2:c.632A>GMANE SELECT
NM_001271985.2:c.-247+3170T>C
NM_001377269.1:c.632A>G
NM_001377270.1:c.632A>G
NM_001424364.1:c.632A>G
NM_031307.4:c.-47+3170T>CMANE SELECT
NM_145014.3:c.632A>G
NP_001128265.1:p.Asp211Gly
NP_001364198.1:p.Asp211Gly
NP_001364199.1:p.Asp211Gly
NP_001411293.1:p.Asp211Gly
NP_659451.1:p.Asp211Gly
NP_659451.1:p.Asp211Gly
NC_000011.9:g.125769895A>G
NM_145014.2:c.632A>G
Q96M11:p.Asp211Gly

Protein change:

D211G; ASP211GLY

Links:

UniProtKB: Q96M11#VAR_031867; OMIM: 610693.0001; dbSNP: rs104894232

NCBI 1000 Genomes Browser:

rs104894232

Molecular consequence:

NM_001271985.2:c.-247+3170T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_031307.4:c.-47+3170T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001134793.2:c.632A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377269.1:c.632A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001377270.1:c.632A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001424364.1:c.632A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_145014.3:c.632A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hydrolethalus syndrome 1 (HLS1)
Identifiers:: MONDO: MONDO:0009365; MedGen: C1856016; Orphanet: 2189; OMIM: 236680

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021352	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2005)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000538043	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 27, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193792	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 27, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15843405, 18648327, 19400947, 19656802 Citation Link,
SCV001423592	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002808806	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 15, 2021)	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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1.

Mee L, Honkala H, Kopra O, Vesa J, Finnilä S, Visapää I, Sang TK, Jackson GR, Salonen R, Kestilä M, Peltonen L.

Hum Mol Genet. 2005 Jun 1;14(11):1475-88. Epub 2005 Apr 20.

PubMed [citation]

PMID:: 15843405

Hydrolethalus syndrome: neuropathology of 21 cases confirmed by HYLS1 gene mutation analysis.

Paetau A, Honkala H, Salonen R, Ignatius J, Kestilä M, Herva R.

J Neuropathol Exp Neurol. 2008 Aug;67(8):750-62. doi: 10.1097/NEN.0b013e318180ec2e.

PubMed [citation]

PMID:: 18648327

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000021352.2

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

Description

Among affected members of 16 Finnish families and 4 isolated individuals with hydrolethalus syndrome (HLS1; 236680), Mee et al. (2005) identified homozygosity for a 1416A-G transition in the HYLS1 gene. The change was predicted to result in substitution of glycine for a highly conserved aspartate-211 residue (D211G). Between 1.1 and 2.5% of the Finnish population are carriers of this mutation.

#	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 Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538043.1

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

Description

The c.632A>G (p.Asp211Gly) missense variant in the HYLS1 gene has been previously reported in 24 affected individuals with autosomal recessive Hydrolethalus syndrome from 16 families in Finland; this variant was shown to co-segregate with disease in these families (Mee et al., 2005). The residue encoded by this variant is positioned at a protease cleavage site, which is lost upon substitution to glycine (Paetau et al., 2008). Functional studies show this variant affects the subcellular localization, sequestering the protein primarily to the nucleus as opposed to the cytoplasm (Mee et al., 2005). This c.632A>G has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP] , 1000 Genomes, and ExAC). Multiple lines of computational evidence suggest a deleterious effect. Therefore, this collective evidence supports the classification of the c.632A>G (p.Asp211Gly) as a recessive Pathogenic variant for Hydrolethalus syndrome.

#	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 Myriad Genetics, Inc., SCV001193792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_001134793.1(HYLS1):c.632A>G(D211G) is classified as pathogenic in the context of hydrolethalus syndrome. Sources cited for classification include the following: PMID 15843405, 18648327, 19400947 and 19656802. Classification of NM_001134793.1(HYLS1):c.632A>G(D211G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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

From Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital, SCV001423592.1

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

Description

[ACMG/AMP: PS3, PM1, PS4_Moderate, PP1, PP3, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

#	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 Fulgent Genetics, Fulgent Genetics, SCV002808806.1

#	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: Sep 29, 2024

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