NM_000520.6(HEXA):c.1307_1308del (p.Ile436fs) AND Tay-Sachs disease

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 19, 2023
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:: RCV000169438.8

Allele description [Variation Report for NM_000520.6(HEXA):c.1307_1308del (p.Ile436fs)]

NM_000520.6(HEXA):c.1307_1308del (p.Ile436fs)

Gene:

HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q23

Genomic location:

Preferred name:

NM_000520.6(HEXA):c.1307_1308del (p.Ile436fs)

HGVS:

NC_000015.10:g.72346550_72346551del
NG_009017.2:g.34630_34631del
NM_000520.6:c.1307_1308delMANE SELECT
NM_001318825.2:c.1340_1341del
NP_000511.2:p.Ile436fs
NP_001305754.1:p.Ile447fs
NC_000015.9:g.72638890_72638891del
NC_000015.9:g.72638891_72638892del
NG_009017.1:g.34630_34631del
NM_000520.4:c.1307_1308delTA
NM_000520.5:c.1307_1308delTA

Protein change:

I436fs

Links:

dbSNP: rs777042785

NCBI 1000 Genomes Browser:

rs777042785

Molecular consequence:

NM_000520.6:c.1307_1308del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318825.2:c.1340_1341del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Tay-Sachs disease (TSD)
Synonyms:: GM2 gangliosidosis, type 1; HexA deficiency; Hexosaminidase alpha-subunit deficiency (variant B); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010100; MedGen: C0039373; Orphanet: 845; OMIM: 272800

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Acinetobacter baumannii strain 578CR 16S ribosomal RNA gene, partial sequence
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220855	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Nov 5, 2014)	unknown	literature only	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000917510	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001584340	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 1833974, 8490625, 22441121, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000220855

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Nov 5, 2014)

unknown

literature only

PubMed (1)
[See all records that cite this PMID]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000917510

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 16, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001584340

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	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	literature only

Citations

PubMed

Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.

Triggs-Raine BL, Akerman BR, Clarke JT, Gravel RA.

Am J Hum Genet. 1991 Nov;49(5):1041-54.

PubMed [citation]

PMID:: 1833974
PMCID:: PMC1683266

Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.

Akli S, Chomel JC, Lacorte JM, Bachner L, Kahn A, Poenaru L.

Hum Mol Genet. 1993 Jan;2(1):61-7. Erratum in: Hum Mol Genet 1993 Apr;2(4):496.

PubMed [citation]

PMID:: 8490625

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000220855.2

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917510.1

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

Description

Variant summary: HEXA c.1307_1308delTA (p.Ile436SerfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251354 control chromosomes (gnomAD). c.1307_1308delTA has been reported in the literature in an individual in homozygous state affected with Tay-Sachs Disease (Zampieri_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001584340.4

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

Description

This sequence change creates a premature translational stop signal (p.Ile436Serfs*7) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs777042785, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 22441121). ClinVar contains an entry for this variant (Variation ID: 189046). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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