VCV000003899.42 - ClinVar

NM_000520.6(HEXA):c.1496G>A (p.Arg499His)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000520.6(HEXA):c.1496G>A (p.Arg499His)

Variation ID: 3899 Accession: VCV000003899.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 72345476 (GRCh38) [ NCBI UCSC ] 15: 72637817 (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	Apr 4, 2013	Oct 20, 2024	Feb 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000520.6:c.1496G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000511.2:p.Arg499His	missense
NM_001318825.2:c.1529G>A	NP_001305754.1:p.Arg510His	missense
NR_134869.3:n.1281G>A		non-coding transcript variant
NC_000015.10:g.72345476C>T
NC_000015.9:g.72637817C>T
NG_009017.2:g.35704G>A
	P06865:p.Arg499His

... more HGVS ... less HGVS

Protein change

R499H, R510H

Other names

Canonical SPDI

NC_000015.10:72345475:C:T

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

Links

ClinGen: CA116501 UniProtKB: P06865#VAR_003244 OMIM: 606869.0010 dbSNP: rs121907956 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.
HEXA		-	-	GRCh38 GRCh37	1141	1175

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.
Gm2-gangliosidosis, juvenile	Pathogenic (1)	no assertion criteria provided	Jan 1, 2003	RCV000004105.4
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2021	RCV000210735.7
Tay-Sachs disease	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV000338961.21
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 8, 2024	RCV000520531.21

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.
Pathogenic (Nov 06, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331828.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 14566483‚ 1833974‚ 2140574‚ 8490625 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Feb 12, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917512.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (4) PubMed: 1301938‚ 22441121‚ 2140574‚ 12202988 Comment: Variant summary: HEXA c.1496G>A (p.Arg499His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: HEXA c.1496G>A (p.Arg499His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant, c.1496G>A, was observed with an allele frequency of 5.7e-05 in 246362 control chromosomes (gnomAD and publication controls). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.7e-05 vs 0.0014), allowing no conclusion about variant significance. The variant, c.1496G>A, has been reported in the literature in multiple compound heterozygote individuals affected with Tay-Sachs Disease, while some present with a subacute phenotype or late-onset (adult and juvenile). Multiple clinical diagnostic laboratories via ClinVar submissions (evaluations performed after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hexosaminidase A deficiency Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001443705.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: This variant has been reported in the literature in the compound heterozygote state in individuals affected with infantile Tay-Sachs disease and in individuals with the … (more) This variant has been reported in the literature in the compound heterozygote state in individuals affected with infantile Tay-Sachs disease and in individuals with the juvenile onset form (PMID 29214523, 31367523, 18490185, 2144098). ClinVar contains an entry for this variant (Variation ID: 3899). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (14/251458) and thus is presumed to be rare. The c.1496G>A (p.Arg499His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1496G>A (p.Arg499His) variant is classified as Likely Pathogenic. (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516540.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tay-Sachs disease Affected status: yes Allele origin: germline	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002562210.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Number of individuals with the variant: 2 Sex: female
Pathogenic (Feb 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tay-Sachs disease (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV003843894.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: A heterozygous missense variation in exon 13 of the HEXA gene that results in the amino acid substitution of Histidine for Arginine at codon 499 … (more) A heterozygous missense variation in exon 13 of the HEXA gene that results in the amino acid substitution of Histidine for Arginine at codon 499 was detected. The observed variant c.1496G>A (p.Arg499His) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less) Clinical Features: Gait ataxia (present) , Slurred speech (present) , Hand tremor (present) , Cerebral cortical atrophy (present) , Thick eyebrow (present) , Staring gaze (present) Age: 10-19 years Sex: male Ethnicity/Population group: Hindu Geographic origin: India Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (Dec 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236152.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Dec 27, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000263008.8 First in ClinVar: Apr 10, 2016 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 1833974‚ 2140574‚ 17015493‚ 18490185‚ 29214523‚ 31367523 Comment: The c.1496G>A (p.R499H) alteration is located in coding exon 13 of the HEXA gene. This alteration results from a G to A substitution at nucleotide … (more) The c.1496G>A (p.R499H) alteration is located in coding exon 13 of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the arginine (R) at amino acid position 499 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (14/251458) total alleles studied. The highest observed frequency was 0.03% (10/30614) of South Asian alleles. This alteration has been reported in multiple individuals with Tay-Sachs disease with a second HEXA alteration (Paw, 1990; Maegawa, 2006; Stepien, 2018; Ou, 2019). This amino acid position is highly conserved in available vertebrate species. The p.R499H amino acid is located in the GH20_HexA_HexB-like domain. Biosynthetic studies of the R499H alteration revealed the synthesis of an abnormal a-subunit which did not associate with the b-subunit. It was not processed into the mature lysosomal form and appeared to be retained and degraded in the endoplasmic reticulum, possibly due to misfolding. However some residual enzyme activity (~3%) was observed (Paw, 1990). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Feb 08, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617692.4 First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024	Comment: Published functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation along with a lower value of the … (more) Published functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation along with a lower value of the solvent-accessible surface area) (PMID: 2140574); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26984043, 1833974, 2140574, 18490185, 29214523, 22441121, 35936646, 34288098, 33240792, 17237499, 34302356, 24767253, 31367523, 19091716) (less)
Pathogenic (Mar 01, 2023)	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: SCV003917408.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: HEXA: PP4:Strong, PM2, PM3, PM5 Number of individuals with the variant: 1
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tay-Sachs disease Affected status: yes Allele origin: germline	3billion Accession: SCV002572637.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (2) PubMed: 29214523‚ 14577003 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003899). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14577003 , 29214523). A different missense change at the same codon (p.Arg499Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003915). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hearing impairment (present)
Pathogenic (May 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835595.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000820054.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 2144098‚ 14577003‚ 17237499 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the HEXA protein (p.Arg499His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the HEXA protein (p.Arg499His). This variant is present in population databases (rs121907956, gnomAD 0.03%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 2144098, 14577003, 17237499). ClinVar contains an entry for this variant (Variation ID: 3899). 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 expected to disrupt HEXA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2003)	no assertion criteria provided Method: literature only	GM2-GANGLIOSIDOSIS, JUVENILE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024271.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 12, 2021	Publications: PubMed (2) PubMed: 2140574‚ 14566483 Comment on evidence: In a patient of mixed Jewish and Scottish/Irish ancestry who had progressively severe neurologic deterioration beginning at age 3 to 5 years and progressing to … (more) In a patient of mixed Jewish and Scottish/Irish ancestry who had progressively severe neurologic deterioration beginning at age 3 to 5 years and progressing to death at age 26, Paw et al. (1990) found a G-to-A transition at nucleotide 1496 resulting in substitution of histidine for arginine at position 499 (R499H) of the alpha subunit. The mutation was present in compound heterozygosity with a common infantile Tay-Sachs allele. This patient had a similarly affected brother. In another patient with juvenile GM2-gangliosidosis (272800), neither this nor the R504H mutation was found, indicating further heterogeneity. Tanaka et al. (2003) found the R499H missense mutation in 1 allele of a Japanese patient with the late infantile form of GM2-gangliosidosis and the R499C mutation (606869.0028) on 1 allele of another Japanese patient with the juvenile form. (less)
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002085655.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Jun 17, 2018)	no assertion criteria provided Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV001132415.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Publications: PubMed (14) PubMed: 22441121‚ 24498621‚ 24767253‚ 16948947‚ 18490185‚ 2140574‚ 1833974‚ 19091716‚ 25557439‚ 8490625‚ 14566483‚ 14577003‚ 17015493‚ 17237499
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Comment:

Variant summary: HEXA c.1496G>A (p.Arg499His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant, c.1496G>A, was observed with an allele frequency of 5.7e-05 in 246362 control chromosomes (gnomAD and publication controls). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.7e-05 vs 0.0014), allowing no conclusion about variant significance. The variant, c.1496G>A, has been reported in the literature in multiple compound heterozygote individuals affected with Tay-Sachs Disease, while some present with a subacute phenotype or late-onset (adult and juvenile). Multiple clinical diagnostic laboratories via ClinVar submissions (evaluations performed after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant has been reported in the literature in the compound heterozygote state in individuals affected with infantile Tay-Sachs disease and in individuals with the juvenile onset form (PMID 29214523, 31367523, 18490185, 2144098). ClinVar contains an entry for this variant (Variation ID: 3899). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (14/251458) and thus is presumed to be rare. The c.1496G>A (p.Arg499His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1496G>A (p.Arg499His) variant is classified as Likely Pathogenic.

Comment:

A heterozygous missense variation in exon 13 of the HEXA gene that results in the amino acid substitution of Histidine for Arginine at codon 499 was detected. The observed variant c.1496G>A (p.Arg499His) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

Comment:

The c.1496G>A (p.R499H) alteration is located in coding exon 13 of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1496, causing the arginine (R) at amino acid position 499 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (14/251458) total alleles studied. The highest observed frequency was 0.03% (10/30614) of South Asian alleles. This alteration has been reported in multiple individuals with Tay-Sachs disease with a second HEXA alteration (Paw, 1990; Maegawa, 2006; Stepien, 2018; Ou, 2019). This amino acid position is highly conserved in available vertebrate species. The p.R499H amino acid is located in the GH20_HexA_HexB-like domain. Biosynthetic studies of the R499H alteration revealed the synthesis of an abnormal a-subunit which did not associate with the b-subunit. It was not processed into the mature lysosomal form and appeared to be retained and degraded in the endoplasmic reticulum, possibly due to misfolding. However some residual enzyme activity (~3%) was observed (Paw, 1990). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Published functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation along with a lower value of the solvent-accessible surface area) (PMID: 2140574); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26984043, 1833974, 2140574, 18490185, 29214523, 22441121, 35936646, 34288098, 33240792, 17237499, 34302356, 24767253, 31367523, 19091716)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003899). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 14577003 , 29214523). A different missense change at the same codon (p.Arg499Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003915). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the HEXA protein (p.Arg499His). This variant is present in population databases (rs121907956, gnomAD 0.03%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 2144098, 14577003, 17237499). ClinVar contains an entry for this variant (Variation ID: 3899). 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 expected to disrupt HEXA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

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
Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling.	Ou L	Molecular genetics and metabolism reports	2019	PMID: 31367523
Haematopoietic Stem Cell Transplantation Arrests the Progression of Neurodegenerative Disease in Late-Onset Tay-Sachs Disease.	Stepien KM	JIMD reports	2018	PMID: 29214523
Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses.	Utz JR	Molecular genetics and metabolism	2015	PMID: 25557439
Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders.	Fernández-Marmiesse A	Orphanet journal of rare diseases	2014	PMID: 24767253
Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening.	Hoffman JD	Molecular genetics & genomic medicine	2013	PMID: 24498621
Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.	Zampieri S	Gene	2012	PMID: 22441121
Late-onset Tay-Sachs disease presenting as a childhood stutter.	Shapiro BE	Journal of neurology, neurosurgery, and psychiatry	2009	PMID: 19091716
Structural consequences of amino acid substitutions causing Tay-Sachs disease.	Ohno K	Molecular genetics and metabolism	2008	PMID: 18490185
Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis.	Maegawa GH	The Journal of biological chemistry	2007	PMID: 17237499
The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported.	Maegawa GH	Pediatrics	2006	PMID: 17015493
Diagnosis and molecular characterization of non-classic forms of Tay-Sachs disease in Brazil.	Rozenberg R	Journal of child neurology	2006	PMID: 16948947
Structural basis of the GM2 gangliosidosis B variant.	Matsuzawa F	Journal of human genetics	2003	PMID: 14577003
Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.	Tanaka A	Journal of human genetics	2003	PMID: 14566483
Molecular analysis of the alpha-N-acetylglucosaminidase gene in seven Japanese patients from six unrelated families with mucopolysaccharidosis IIIB (Sanfilippo type B), including two novel mutations.	Tanaka A	Journal of human genetics	2002	PMID: 12202988
Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.	Akli S	Human molecular genetics	1993	PMID: 8490625
A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies.	Akerman BR	Human mutation	1992	PMID: 1301938
Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.	Triggs-Raine BL	American journal of human genetics	1991	PMID: 1833974
A new point mutation in the beta-hexosaminidase alpha subunit gene responsible for infantile Tay-Sachs disease in a non-Jewish Caucasian patient (a Kpn mutant).	Tanaka A	American journal of human genetics	1990	PMID: 2144098
Juvenile GM2 gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the alpha-subunit of beta-hexosaminidase.	Paw BH	The Journal of biological chemistry	1990	PMID: 2140574
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA	-	-	-	-
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Text-mined citations for rs121907956 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000520.6(HEXA):c.1496G>A (p.Arg499His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121907956 ...