VCV000554039.85 - ClinVar

NM_000520.6(HEXA):c.1074-7_1074-3del

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000520.6(HEXA):c.1074-7_1074-3del

Variation ID: 554039 Accession: VCV000554039.85

Type and length

Microsatellite, 5 bp

Location

Cytogenetic: 15q23 15: 72347761-72347765 (GRCh38) [ NCBI UCSC ] 15: 72640102-72640106 (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	May 1, 2024	May 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000520.6:c.1074-7_1074-3del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001318825.2:c.1107-7_1107-3del		intron variant
NC_000015.10:g.72347765AGGAG[1]
NC_000015.9:g.72640106AGGAG[1]
NG_009017.2:g.33410TCTCC[1]

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000015.10:72347760:GGAGAGGAGAGGAG:GGAGAGGAG

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.

Links

OMIM: 606869.0021 dbSNP: rs759219683 VarSome

Comment on variant

NCBI staff provided an HGVS expression for allelic variant 606869.0021 based on finding only one TCTCC sequence in intron 9.

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.
Tay-Sachs disease	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 12, 2023	RCV000669592.72
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 20, 2023	RCV001584543.11

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 06, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794361.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 1833974
Uncertain significance (Jan 20, 2023)	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: SCV001821429.3 First in ClinVar: Sep 08, 2021 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 10571007‚ 1833974 Comment: Variant summary: HEXA c.1074-7_1074-3delTCTCC removes 5 nucleotides, thus shortening the length of the polypyrimidine tract located in intron 9, and therefore could affect mRNA splicing, … (more) Variant summary: HEXA c.1074-7_1074-3delTCTCC removes 5 nucleotides, thus shortening the length of the polypyrimidine tract located in intron 9, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 3' acceptor site, while one predicts the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes (gnomAD). c.1074-7_1074-3delTCTCC has been reported in the literature in a family in 3 individuals affected with Tay-Sachs Disease, who also carried a pathogenic variant in trans (Triggs-Raine_1991). Though the authors of this study noted that their preliminary results showed that this mutation results in aberrant splicing, they also added that further studies are required to confirm these findings. Other variants shortening the polypyrimidine tract in intron 12 of the HEXA gene were demonstrated to result in exon skipping, when an exonic variant was also present at the first position of exon 13 (Fu_2011), however these data do not provide clear conclusions about the effect of the variant of interest. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Likely pathogenic (May 12, 2023)	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: SCV004297642.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 1833974 Comment: ClinVar contains an entry for this variant (Variation ID: 554039). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 1833974). In at least … (more) ClinVar contains an entry for this variant (Variation ID: 554039). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 1833974). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs759219683, gnomAD 0.0009%). This sequence change falls in intron 9 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Affects (Nov 01, 1991)	no assertion criteria provided Method: literature only	TAY-SACHS DISEASE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024281.64 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 1833974 Comment on evidence: Triggs-Raine et al. (1991) sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the … (more) Triggs-Raine et al. (1991) sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the PCR-dependent amplification of each exon and splice junction sequence. Five novel mutations from Tay-Sachs disease (272800) patients were detected as well as 2 mutations that had previously been reported. The 5 novel mutations were a 5-bp deletion of TCTCC in IVS9; a 2-bp deletion of TG in exon 5; 78G-A, giving a stop codon in exon 1; 533G-T in exon 5, producing the third amino acid substitution detected at this site; and G to C at position 1 of IVS2, expected to produce abnormal splicing. The 2 previously reported mutations were 1496G-A in exon 13 (606869.0010) and a 4-bp insertion in exon 11 (606869.0001). (less)

Comment:

Variant summary: HEXA c.1074-7_1074-3delTCTCC removes 5 nucleotides, thus shortening the length of the polypyrimidine tract located in intron 9, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 3' acceptor site, while one predicts the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes (gnomAD). c.1074-7_1074-3delTCTCC has been reported in the literature in a family in 3 individuals affected with Tay-Sachs Disease, who also carried a pathogenic variant in trans (Triggs-Raine_1991). Though the authors of this study noted that their preliminary results showed that this mutation results in aberrant splicing, they also added that further studies are required to confirm these findings. Other variants shortening the polypyrimidine tract in intron 12 of the HEXA gene were demonstrated to result in exon skipping, when an exonic variant was also present at the first position of exon 13 (Fu_2011), however these data do not provide clear conclusions about the effect of the variant of interest. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Comment:

ClinVar contains an entry for this variant (Variation ID: 554039). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 1833974). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs759219683, gnomAD 0.0009%). This sequence change falls in intron 9 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
Biochemical consequences of mutations causing the GM2 gangliosidoses.	Mahuran DJ	Biochimica et biophysica acta	1999	PMID: 10571007
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

Text-mined citations for rs759219683 ...

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_000520.6(HEXA):c.1074-7_1074-3del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs759219683 ...