VCV000362377.21 - ClinVar

NM_177924.5(ASAH1):c.620A>T (p.Tyr207Phe)

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.

(12)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_177924.5(ASAH1):c.620A>T (p.Tyr207Phe)

Variation ID: 362377 Accession: VCV000362377.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p22 8: 18062307 (GRCh38) [ NCBI UCSC ] 8: 17919816 (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	Dec 6, 2016	May 1, 2024	Apr 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_177924.5:c.620A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_808592.2:p.Tyr207Phe	missense
NM_001127505.3:c.602A>T	NP_001120977.1:p.Tyr201Phe	missense
NM_001363743.2:c.425A>T	NP_001350672.1:p.Tyr142Phe	missense
NM_004315.6:c.668A>T	NP_004306.3:p.Tyr223Phe	missense
NC_000008.11:g.18062307T>A
NC_000008.10:g.17919816T>A
NG_008985.2:g.27692A>T

... more HGVS ... less HGVS

Protein change

Y223F, Y207F, Y201F, Y142F

Other names

p.Tyr207Phe

Canonical SPDI

NC_000008.11:18062306:T: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.

0.00040 (A)

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

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

The Genome Aggregation Database (gnomAD) 0.00049

Trans-Omics for Precision Medicine (TOPMed) 0.00049

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Links

ClinGen: CA4650766 dbSNP: rs150268016 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.
ASAH1		-	-	GRCh38 GRCh37	885	1020

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.
Childhood epilepsy with centrotemporal spikes	Pathogenic (1)	no assertion criteria provided	Jan 1, 2017	RCV000656012.2
not provided	Uncertain significance (7)	criteria provided, multiple submitters, no conflicts	Apr 5, 2023	RCV000853063.13
Farber lipogranulomatosis Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	not provided (1)	no classification provided	-	RCV000709958.1
Farber lipogranulomatosis	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2018	RCV000332641.6
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 13, 2022	RCV002523651.2

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.
Uncertain significance (Oct 30, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000994993.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Comment: The Y207F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y207F … (more) The Y207F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y207F variant is observed in 95/126,696 (0.07%) alleles from individuals of European background (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Farber lipogranulomatosis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000472716.3 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Dec 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Farber lipogranulomatosis Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001526320.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001513044.2 First in ClinVar: Mar 14, 2021 Last updated: Mar 26, 2023	Comment: This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 207 of the ASAH1 protein (p.Tyr207Phe). … (more) This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 207 of the ASAH1 protein (p.Tyr207Phe). This variant is present in population databases (rs150268016, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ASAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 362377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASAH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 12, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003799564.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023
Uncertain significance (Apr 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224135.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Number of individuals with the variant: 2
Uncertain significance (Jun 13, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003680961.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.620A>T (p.Y207F) alteration is located in exon 8 (coding exon 8) of the ASAH1 gene. This alteration results from a A to T substitution … (more) The c.620A>T (p.Y207F) alteration is located in exon 8 (coding exon 8) of the ASAH1 gene. This alteration results from a A to T substitution at nucleotide position 620, causing the tyrosine (Y) at amino acid position 207 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Pathogenic (Jan 01, 2017)	no assertion criteria provided Method: case-control	Childhood epilepsy with centrotemporal spikes Affected status: yes Allele origin: germline	Bioinformatics Core, Luxembourg Center for Systems Biomedicine Study: EUROEPINOMICS COGIE Accession: SCV000588288.1 First in ClinVar: Jun 01, 2018 Last updated: Jun 01, 2018	Publications: PubMed (1) PubMed: 29358611 Comment: CAADphred>15
Uncertain significance (-)	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: SCV001744633.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919194.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	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: SCV001974284.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: phenotyping only	Farber lipogranulomatosis Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Affected status: unknown Allele origin: paternal	GenomeConnect, ClinGen Accession: SCV000840320.1 First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018	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: Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Overgrowth (present) , Abnormality of the skull (present) , Abnormality of … (more) Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Overgrowth (present) , Abnormality of the skull (present) , Abnormality of the oral cavity (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Cognitive impairment (present) , Morphological abnormality of the central nervous system (present) , Autistic behavior (present) , Short attention span (present) , Obsessive-compulsive behavior (present) , Generalized abnormality of skin (present) , Joint hypermobility (present) , Abnormality of muscle physiology (present) , EMG abnormality (present) , Syncope (present) , Abnormal EKG (present) , Arrhythmia (present) , Abnormality of the large intestine (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Abnormal inflammatory response (present) , Abnormality of leukocytes (present) , Abnormality of erythrocytes (present) , Abnormality of thrombocytes (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: Courtagen Diagnostics Laboratory,Courtagen Life Sciences Date variant was reported to submitter: 2017-01-26 Testing laboratory interpretation: Uncertain significance
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Comment:

The Y207F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y207F variant is observed in 95/126,696 (0.07%) alleles from individuals of European background (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 207 of the ASAH1 protein (p.Tyr207Phe). This variant is present in population databases (rs150268016, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ASAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 362377). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASAH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.620A>T (p.Y207F) alteration is located in exon 8 (coding exon 8) of the ASAH1 gene. This alteration results from a A to T substitution at nucleotide position 620, causing the tyrosine (Y) at amino acid position 207 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.	Bobbili DR	European journal of human genetics : EJHG	2018	PMID: 29358611

Text-mined citations for rs150268016 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_177924.5(ASAH1):c.620A>T (p.Tyr207Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150268016 ...