VCV000194706.57 - ClinVar

NM_000414.4(HSD17B4):c.1471G>A (p.Ala491Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000414.4(HSD17B4):c.1471G>A (p.Ala491Thr)

Variation ID: 194706 Accession: VCV000194706.57

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q23.1 5: 119515014 (GRCh38) [ NCBI UCSC ] 5: 118850709 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 8, 2016	Dec 22, 2024	Nov 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000414.4:c.1471G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000405.1:p.Ala491Thr	missense
NM_001199291.3:c.1546G>A	NP_001186220.1:p.Ala516Thr	missense
NM_001199292.2:c.1417G>A	NP_001186221.1:p.Ala473Thr	missense
NM_001292027.2:c.1399G>A	NP_001278956.1:p.Ala467Thr	missense
NM_001292028.2:c.1051G>A	NP_001278957.1:p.Ala351Thr	missense
NM_001374497.1:c.1462G>A	NP_001361426.1:p.Ala488Thr	missense
NM_001374498.1:c.1399G>A	NP_001361427.1:p.Ala467Thr	missense
NM_001374499.1:c.1144G>A	NP_001361428.1:p.Ala382Thr	missense
NM_001374500.1:c.1030G>A	NP_001361429.1:p.Ala344Thr	missense
NM_001374501.1:c.1060G>A	NP_001361430.1:p.Ala354Thr	missense
NM_001374502.1:c.1060G>A	NP_001361431.1:p.Ala354Thr	missense
NM_001374503.1:c.1060G>A	NP_001361432.1:p.Ala354Thr	missense
NR_164653.1:n.1568G>A		non-coding transcript variant
NR_164654.1:n.1836G>A		non-coding transcript variant
NC_000005.10:g.119515014G>A
NC_000005.9:g.118850709G>A
NG_008182.1:g.67562G>A
	P51659:p.Ala491Thr

... more HGVS ... less HGVS

Protein change

A491T, A516T, A351T, A467T, A473T, A488T, A344T, A382T, A354T

Other names

Canonical SPDI

NC_000005.10:119515013:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00200 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00200

1000 Genomes Project 30x 0.00203

Exome Aggregation Consortium (ExAC) 0.00312

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00392

Trans-Omics for Precision Medicine (TOPMed) 0.00418

Links

ClinGen: CA201313 UniProtKB: P51659#VAR_052312 dbSNP: rs28943591 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HSD17B4		-	-	GRCh38 GRCh37	1288	1344

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jul 27, 2022	RCV000175136.19
Bifunctional peroxisomal enzyme deficiency Perrault syndrome 1	not provided (1)	no classification provided	-	RCV000509557.10
not provided	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Nov 1, 2024	RCV000224951.41
Perrault syndrome 1	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000298832.13
Bifunctional peroxisomal enzyme deficiency	Likely benign (2)	criteria provided, single submitter	Jan 13, 2018	RCV000353669.14
Bifunctional peroxisomal enzyme deficiency Perrault syndrome	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001084433.16

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely Benign (Aug 19, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280844.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Comment: Converted during submission to Likely benign.
Benign (Dec 07, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000714003.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Mar 30, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000226571.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HSD17B4 http://www.sciencedirect.com/sci… http://www.sciencedirect.com/science/article/pii/S2214426914000822# Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Benign (Nov 24, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000269157.2 First in ClinVar: May 29, 2016 Last updated: Apr 09, 2018	Comment: Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of … (more) Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943591). (less) Number of individuals with the variant: 7
Likely benign (Jul 15, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001144222.1 First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Perrault syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000452129.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Bifunctional peroxisomal enzyme deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000452130.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jul 27, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002570591.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three … (more) Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251252 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Oct 16, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472252.3 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Perrault syndrome Bifunctional peroxisomal enzyme deficiency Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001113671.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005220617.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Nov 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001154490.28 First in ClinVar: Feb 03, 2020 Last updated: Dec 22, 2024	Comment: HSD17B4: BP4, BS2 Number of individuals with the variant: 17
Benign (Jan 12, 2020)	no assertion criteria provided Method: clinical testing	Bifunctional peroxisomal enzyme deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457298.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963293.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001969210.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (-)	no classification provided Method: phenotyping only	Bifunctional peroxisomal enzyme deficiency Perrault syndrome 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607089.2 First in ClinVar: Oct 16, 2017 Last updated: Jun 17, 2024	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Decreased fetal movement (present) , Abnormal delivery (present) , Short stature (present) , Abnormality of the neck (present) , Oral-pharyngeal dysphagia (present) , Abnormality of … (more) Decreased fetal movement (present) , Abnormal delivery (present) , Short stature (present) , Abnormality of the neck (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Ptosis (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of digit (present) , Abnormality of facial musculature (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Feeding difficulties (present) , Abnormality of esophagus morphology (present) , Abnormality of the large intestine (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2015-01-27 Testing laboratory interpretation: Uncertain significance
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

Ala516Thr in exon 18 of HSD17B4: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (48/8596) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs28943591).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Variant summary: HSD17B4 c.1471G>A (p.Ala491Thr) results in a non-conservative amino acid change located in the MaoC-like dehydratase domain (IPR002539) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 251252 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HSD17B4 causing D-Bifunctional Protein Deficiency phenotype (0.003), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HSD17B4	-	-	-	-
http://www.sciencedirect.com/science/article/pii/S2214426914000822#	-	-	-	-

Text-mined citations for rs28943591 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000414.4(HSD17B4):c.1471G>A (p.Ala491Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28943591 ...