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NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs) AND Tay-Sachs disease

Germline classification:
Pathogenic (22 submissions)
Last evaluated:
Jan 28, 2024
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:
RCV000004093.106

Allele description

NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs)

Gene:
HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
15q23
Genomic location:
Preferred name:
NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs)
Other names:
1278insTATC; +TATC1278
HGVS:
  • NC_000015.10:g.72346580_72346583dup
  • NG_009017.2:g.34597_34600dup
  • NG_009017.3:g.34431_34434dup
  • NM_000520.6:c.1274_1277dupMANE SELECT
  • NM_001318825.2:c.1307_1310dup
  • NP_000511.2:p.Tyr427fs
  • NP_001305754.1:p.Tyr438fs
  • NC_000015.9:g.72638920_72638921insGATA
  • NC_000015.9:g.72638921_72638924dup
  • NG_009017.1:g.34597_34600dup
  • NM_000520.4:c.1274_1277dup
  • NM_000520.4:c.1274_1277dupTATC
  • NM_000520.5:c.1274_1277dup
  • NM_000520.5:c.1274_1277dupTATC
  • NP_000511.2:p.Tyr42fs
  • c.1274_1277dupTATC (p.Tyr427Ilefs*5)
  • p.Y427IfsX5
Protein change:
Y427fs
Links:
OMIM: 606869.0001; dbSNP: rs387906309
NCBI 1000 Genomes Browser:
rs387906309
Molecular consequence:
  • NM_000520.6:c.1274_1277dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001318825.2:c.1307_1310dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000024259OMIM
no assertion criteria provided
Pathogenic
(Mar 1, 2004)
germlineliterature only

PubMed (7)
[See all records that cite these PMIDs]

SCV000218958Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 28, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000247559Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 15, 2014)
germlineclinical testing

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

SCV000328765Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 27, 2022)
unknownclinical testing

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

SCV000494223Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
no assertion criteria provided
Pathogenic
(Sep 11, 2014)
germlineresearch

PubMed (3)
[See all records that cite these PMIDs]

SCV000538041Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 26, 2015)
germlineclinical testing

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

SCV000584094HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha
criteria provided, single submitter

(HA_assertions_20150911)
Pathogenic
(Jul 10, 2014)
unknown, paternalresearch

HA_assertions_20150911.pdf,

Citation Link,

SCV000680255Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
criteria provided, single submitter

(Classification criteria August 2017)
Pathogenic
(Nov 8, 2017)
maternalclinical testing

Citation Link,

SCV000697162Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Aug 21, 2017)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000712205Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(May 18, 2017)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000914692Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
Pathogenic
(Aug 29, 2018)
germlineclinical testing

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

Citation Link,

SCV001142451Reproductive Health Research and Development, BGI Genomics
no assertion criteria provided
Pathogenic
(Jan 6, 2020)
germlinecuration

SCV001193865Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))
Pathogenic
(Oct 18, 2019)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002024978Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 18, 2021)
germlineclinical testing

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

SCV002085670Natera, Inc.
no assertion criteria provided
Pathogenic
(Mar 17, 2017)
germlineclinical testing

SCV002506704New York Genome Center - CSER-NYCKidSeq
criteria provided, single submitter

(NYGC Assertion Criteria 2020)
Pathogenic
(Jun 7, 2021)
inheritedclinical testing

Citation Link,

SCV002526129Institute of Human Genetics, University Hospital Muenster
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 30, 2022)
unknownclinical testing

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

SCV002567942Daryl Scott Lab, Baylor College of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Aug 22, 2022)
maternalclinical testing

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

SCV002579636MGZ Medical Genetics Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 3, 2021)
germlineclinical testing

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

SCV002768489Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 31, 2022)
germlineclinical testing

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

SCV004032467Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 29, 2023)
germlineclinical testing

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

SCV004242410Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 2, 2024)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedinheritedunknown1not providednot provided1not providedclinical testing
not providedpaternalyes1not providednot provided1not providedresearch
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing
not providedunknownyes2not providednot provided2not providedclinical testing, research
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedmaternalyes1not providednot provided1not providedclinical testing
not providedmaternalunknown1not providednot providednot providednot providedclinical testing
not providedunknownno1not providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
Indiangermlineyes1not providednot provided1not providedresearch

Citations

PubMed

A deletion involving Alu sequences in the beta-hexosaminidase alpha-chain gene of French Canadians with Tay-Sachs disease.

Myerowitz R, Hogikyan ND.

J Biol Chem. 1987 Nov 15;262(32):15396-9.

PubMed [citation]
PMID:
2824459

Diagnostic heteroduplexes: simple detection of carriers of a 4-bp insertion mutation in Tay-Sachs disease.

Triggs-Raine BL, Gravel RA.

Am J Hum Genet. 1990 Jan;46(1):183-4. No abstract available.

PubMed [citation]
PMID:
2294750
PMCID:
PMC1683528
See all PubMed Citations (35)

Details of each submission

From OMIM, SCV000024259.64

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (7)

Description

Myerowitz and Costigan (1988) demonstrated that the most frequent DNA lesion in Tay-Sachs disease (272800) of Ashkenazi Jews is a homozygous 4-bp insertion in exon 11. This mutation introduces a premature termination signal in exon 11, resulting in a deficiency of mRNA. Using a dot-blot assay to screen patients and heterozygous carriers for the insertion mutation, Myerowitz and Costigan (1988) found the lesion in about 70% of carriers tested, thus identifying it as the most frequent defect underlying Tay-Sachs disease in the Ashkenazi Jewish population. Triggs-Raine and Gravel (1990) showed that this insertion mutation of only 4 bp can be detected by the formation of heteroduplexes. This mutation causes a frameshift and a termination codon 9 nucleotides downstream. By site-directed mutagenesis, Nishimoto et al. (1991) examined the basis of the paradox that the mutant gene with the 4-base insertion in exon 11 is transcribed normally but the mRNA is essentially undetectable. They found no evidence of interference with normal splicing of the transcript and the mutation did not destabilize properly spliced mRNA. Thus, the studies left open the question of the mechanism of the mutation. The possibility was mentioned that another still unidentified abnormality in the same allele may be responsible for the nearly complete absence of mRNA.

There appears to be an increased frequency of TSD in the Cajun population of southwest Louisiana which numbers less than one million persons. McDowell et al. (1992) reported that in the previous 3 decades, at least 8 infants from 6 apparently unrelated Cajun families had been identified. They found that the mutation in 11 of 12 of the TSD alleles in these 6 families was the exon 11 insertion present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The remaining allele was a single-base transition in the donor splice site of intron 9 (606869.0033). To trace the origins of these 2 mutations in the Cajun population, the TSD carrier status was determined enzymatically in 90 members of 4 of the 6 families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggested that this mutation has been in the Cajun population since its founding and that it may be widely distributed within the population. In contrast, the intron 9 mutation was apparently introduced later and is probably limited to a few Louisiana families. Zlotogora (1993) argued that 2 mutations would not be unexpected in the Cajun population. Thurmon (1993) gave a historical account of the 'Jews of Acadiana.' He indicated that the Jews were assimilated into the Acadian culture and suggested that this was the source of the Tay-Sachs genes. He also pointed out that about the same time Jewish merchants began to arrive in Acadiana, the French Revolution produced an influx of non-Acadian French immigrants. Many were of aristocratic lineage and held themselves aloof from the Acadians.

This mutation is alternatively designated 1277TATC or 1278insTATC. See 606869.0054.

To investigate the genetic history of the 1278insTATC mutation, the most frequent cause of Tay-Sachs disease in Ashkenazi Jews, Frisch et al. (2004) identified a conserved haplotype in 1278insTATC chromosomes for 55 unrelated Ashkenazi Jewish individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When 2 methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for study of the decay of LD over time, the estimated age of the insertion was found to be 40 +/- 12 generations (95% confidence interval, 30 to 50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th or 9th century. This corresponds with the demographic expansion of Ashkenazi Jews in central Europe, following the founding of the Ashkenazi settlement in the early Middle Ages. The results were also consistent with the geographic distribution of the mutation and with the coalescent times of mutations causing 2 other lysosomal storage diseases frequent in Ashkenazi Jews: Gaucher disease (230800) and mucolipidosis IV (252650). Evidence for the absence of a heterozygote advantage of the mutation was provided by comparison between the estimated age of 1278insTATC and the probability of the current Ashkenazi Jewish frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust and parsimonious hypothesis explaining the spread of 1278insTATC-related TSD in Ashkenazi Jewish individuals.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000218958.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Tyr427Ilefs*5) 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 (rs387906309, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Tay-Sachs disease (PMID: 2848800, 16352452, 20301397, 24518553, 25287655). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2848800, 22975760). This variant is also known as c.1277_1278insTATC. ClinVar contains an entry for this variant (Variation ID: 3889). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genetic Services Laboratory, University of Chicago, SCV000247559.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV000328765.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000494223.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Indian1not providednot providedresearch PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1Bloodnot provided1not providednot providednot provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538041.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The c.1274_1277dupTATC, (p.Tyr427Ilefs*5) is a known frameshift variant that has been shown to result in the absence of mRNA. To that effect, the majority of pathogenic variants in the Ashkenazi Jewish TSD are null alleles, making it a common mechanism of disease. Moreover, this 4 basepair insertion variant has been reported in the majority of affected individuals of Ashkenazi Jewish ancestry (Myerowitz and Costigan, 1988), and has not been seen in the normal population databases (1000 Genomes, ExAc, and Exome Sequencing Project [ESP]). In summary, this variant is best classified as a recessive pathogenic variant for Tay-Sachs disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000584094.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearchnot provided
2not provided1not providednot providedresearchnot provided
3not provided1not providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyes1not providednot provided1not providednot providednot provided
2unknownyes1not providednot provided1not providednot providednot provided
3paternalyes1not providednot provided1not providednot providednot provided

From Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München, SCV000680255.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyes1bloodnot provided1not providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697162.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: This c.1274_1277dupTATC (p.Tyr427Ilefs) results in a premature termination codon, predicted to cause a truncated or absent HEXA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study found less than 5% b-Hexosaminidase activity in leukocytes from a patient with Tay-Sachs disease carrying this variant in compound heterozygosity with p.R510H (not in our internal database)(Udwadia-Hedge_2017). This variant was found in the large control database ExAC in 92/121426 control chromosomes at a frequency of 0.0007577, which does not exceed the maximal expected frequency of a pathogenic allele (0.0013975) in this gene. This variant has been reported as a common pathogenic variant found especially in Ashkenazi Jews population with consistent clinical and genetic data (Myerowitz_1988, Jamali_2014, Zampieri_2012). Multiple clinical labs as well as reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712205.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (12)

Description

The p.Tyr427IlefsX5 (NM_000520.4 c.1274_1277dupTATC) variant in HEXA is a common pathogenic variant that has been reported in many compound heterozygous and hom ozygous individuals with Tay-Sachs disease (Myerowitz 1988, Montalvo 2005, Scott 2010, Gort 2012, Zampieri 2012, Jamail 2014). It has been reported in ClinVar ( Variation ID#3889) as pathogenic by multiple laboratories. This variant has been identified in 1.3% (135/10152) of Ashkenazi Jewish chromosomes and 0.03% (48/12 6682) of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs387906309). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 427 and le ads to a premature termination codon 5 amino acids downstream. This alteration i s then predicted to lead to a truncated or absent protein. Biallelic loss of fun ction in the HEXA gene is an established disease mechanism for Tay-Sachs disease . In summary, this variant meets criteria to be classified as pathogenic for Ta y-Sachs disease in an autosomal recessive manner based upon a predicted null eff ect and its biallelic occurrence in individuals with this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Illumina Laboratory Services, Illumina, SCV000914692.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The HEXA c.1274_1277dupTATC (p.Tyr427IlefsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Tyr427IlefsTer5 variant has been identified in eight probands in a homozygous state, two probands in a compound heterozygous state and in five probands with unknown zygosity (Myerowitz et al. 1988; McDowell et al. 1992; Jamali et al. 2014; Sheth et al. 2014). The c.1274_1277dupTATC (p.Tyr427IlefsTer5) the most common HEXA variant in the Ashkenazi Jewish population and accounts for approximately 80% of variant HEXA alleles in this population (Kaback et al. 2011). Segregation of the variant with the disease has been shown in at least two families (Myerowitz et al. 1988). The variant was found in 69 of 2238 controls in a heterozygous state and is reported at a frequency of 0.00157 in the European American population of the Exome Sequencing Project. Due to the potential impact of frameshift variants, the p.Tyr427IlefsTer5 variant is classified as pathogenic for hexosaminidase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Reproductive Health Research and Development, BGI Genomics, SCV001142451.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

NM_000520.4:c.1274_1277dupTATC in the HEXA gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located at the 11th exon (14 exons in the NM_000520.4 transcript), therefore, it is predicted to lead nonsense-mediated mRNA decay. The c.1274_1277dupTATC (p.Tyr427Ilefs*5) variant has been reported multiple times and is determiend as the most common disease-causing variant in the Ashkenazi Jewis (PMID: 20672374). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PS4; PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Myriad Genetics, Inc., SCV001193865.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

NM_000520.4(HEXA):c.1274_1277dupTATC(Y427Ifs*5) is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that the Y427Ifs*5 variant is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 2848800, 1307230, 1830584, 11463833, and 14727180. Classification of NM_000520.4(HEXA):c.1274_1277dupTATC(Y427Ifs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002024978.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV002085670.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From New York Genome Center - CSER-NYCKidSeq, SCV002506704.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedunknown1not providednot provided1not providednot providednot provided

From Institute of Human Genetics, University Hospital Muenster, SCV002526129.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

ACMG categories: PVS1,PS4,PP5,BS1

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnonot providedbloodnot provided1not providednot providednot provided

From Daryl Scott Lab, Baylor College of Medicine, SCV002567942.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providednot provided1not providednot providednot provided

From MGZ Medical Genetics Center, SCV002579636.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768489.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (210 heterozygotes, 0 homozygotes). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn, SCV004032467.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004242410.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Criteria applied: PVS1,PM3_VSTR,PM2_SUP

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 6, 2024