rs28942073
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBS1_Supporting
The NM_000521.4(HEXB):βc.1250C>Tβ(p.Pro417Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,614,018 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.00047 ( 0 hom., cov: 32)
Exomes π: 0.00081 ( 3 hom. )
Consequence
HEXB
NM_000521.4 missense
NM_000521.4 missense
Scores
4
7
7
Clinical Significance
Conservation
PhyloP100: 1.97
Genes affected
HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PP5
Variant 5-74718804-C-T is Pathogenic according to our data. Variant chr5-74718804-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74718804-C-T is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000809 (1182/1461788) while in subpopulation EAS AF= 0.00378 (150/39690). AF 95% confidence interval is 0.00329. There are 3 homozygotes in gnomad4_exome. There are 565 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HEXB | NM_000521.4 | c.1250C>T | p.Pro417Leu | missense_variant | 11/14 | ENST00000261416.12 | NP_000512.2 | |
| HEXB | NM_001292004.2 | c.575C>T | p.Pro192Leu | missense_variant | 11/14 | NP_001278933.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HEXB | ENST00000261416.12 | c.1250C>T | p.Pro417Leu | missense_variant | 11/14 | 1 | NM_000521.4 | ENSP00000261416.7 |
Frequencies
GnomAD3 genomes 0.000473 AC: 72AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000589 AC: 148AN: 251338Hom.: 0 AF XY: 0.000655 AC XY: 89AN XY: 135842
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GnomAD4 exome AF: 0.000809 AC: 1182AN: 1461788Hom.: 3 Cov.: 32 AF XY: 0.000777 AC XY: 565AN XY: 727202
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GnomAD4 genome 0.000473 AC: 72AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36AN XY: 74430
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sandhoff disease Pathogenic:10
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 31, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 417 of the HEXB protein (p.Pro417Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs28942073, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Sandhoff disease (PMID: 1531140, 7557963, 21150067, 22789865, 24263030). It has also been observed to segregate with disease in related individuals. This variant is also known as Pro405Leu. ClinVar contains an entry for this variant (Variation ID: 3878). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HEXB protein function. Studies have shown that this missense change results in exon 11 skipping and the activation of a cryptic splice site and introduces a premature termination codon (PMID: 1386607, 1531140). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000521.3(HEXB):c.1250C>T(P417L) is classified as pathogenic in the context of Sandhoff disease. Sources cited for classification include the following: PMID 1386607, 7557963, 24263030, 17237499, 1531140, 23127958, 22789865 and 21150067. Classification of NM_000521.3(HEXB):c.1250C>T(P417L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.Γ’β¬Ε‘ΓβΓΒΆΓ’ΛΕ‘ΓβΓ’ΛΕ‘ΓΒ£ - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 25, 2017 | The HEXB c.1250C>T (p.Pro417Leu) missense variant has been reported in a total of nine individuals with Sandhoff disease, including one homozygote and eight compound heterozygotes (McInnes et al. 1992; Wakamatsu et al. 1992; Gomez-Lira et al. 1995; Ahn et al. 2010; Kang et al. 2013; Yamada et al. 2013; Grunseich et al. 2015). Three asymptomatic and one minimally symptomatic siblings of a mildly affected, 57 year-old compound heterozygote carrying the p.Pro417Leu variant in trans with a null variant, each with total hexosaminidase levels within the range expected for Sandhoff disease, also carried the variant in a compound heterozygous state (McInnes et al. 1992). The variant was additionally found in a heterozygous state in seven unaffected individuals. The variant was absent from 36 controls and is reported at a frequency of 0.00162 in the East Asian population of the Exome Aggregation Consortium. Functional studies in patient fibroblasts showed that the variant resulted in less than 10% of mRNA levels compared to wild type, absent or severely reduced hexosaminidase B activity, and a reduced level of hexosaminidase A activity (McInnes et al. 1992; Wakamatsu et al. 1992; Kang et al. 2013; Yamada et al. 2013; Grunseich et al. 2015). RT-PCR experiments in patient and transfected COS7 cells demonstrated that the p.Pro417Leu variant resulted in aberrant splicing, inhibition of recognition of the normal splice site, and activation of a cryptic splice site (Wakamatsu et al. 1992). Based on the collective evidence, the p.Pro417Leu variant is classified as pathogenic for Sandhoff disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2020 | Variant summary: HEXB c.1250C>T (p.Pro417Leu) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, the variant has been shown to lead to aberant mRNA splicing (Wakamatsu_1992, Mcinnes_1992). The variant allele was found at a frequency of 0.00059 in 251338 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (0.00059 vs 0.0015). c.1250C>T has been reported in the literature in multiple individuals affected with Sandhoff Disease (Mcinnes_1992, Wakamatsu_1992, Gort_2012, Grunseich_2015). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | 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 Sandhoff disease, infantile, juvenile, and adult forms (MIM#268800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Splice variant proven to affect splicing of the transcript by RNA studies, resulting in two protein products (p.(Leu415Ilefs*1, p.(Leu415Valfs*56)) (PMID: 1531140). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (159 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, PMID: 29448188). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with Sandhoff disease (ClinVar, PMID: 1531140, 29448188). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 21, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | HEXB: PM3:Very Strong, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 04, 2024 | PP1, PP4, PM3_strong, PS3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2023 | Published functional studies demonstrate misspliced unstable mRNA and reduced level of enzyme activity (PMID: 1386607); 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: 2147027, 29448188, 1386607, 24263030, 7557963, 21150067, 1531140, 31589614, 34670123, 31847883, 17237499, 22789865, 34503567, 23127958, 25736553) - |
HEXB-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2024 | The HEXB c.1250C>T variant is predicted to result in the amino acid substitution p.Pro417Leu. This variant (also known to the literature as c.1214C>T, p.Pro405Leu) has been reported in homozygous and compound heterozygous state in several individulas with Sandhoff disease (Gomez-Lira et al. 1995. PubMedID: 7557963; Ahn et al. 2010. PubMedID: 21150067; Gort et al 2012. PubMed ID: 22789865; Wakamatsu et al. 1992. PubMed ID: 1531140; McInnes et al. 1992 Pubmed ID: 1386607). Functional studies showed that the c.1250C>T variant results in defective splicing (Wakamatsu et al. 1992. PubMed ID: 1531140; McInnes et al. 1992 Pubmed ID: 1386607). This variant is reported in 0.098% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2022 | The c.1250C>T (p.P417L) alteration is located in exon 11 (coding exon 11) of the HEXB gene. This alteration results from a C to T substitution at nucleotide position 1250, causing the proline (P) at amino acid position 417 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.06% (159/282736) total alleles studied. The highest observed frequency was 0.1% (127/129062) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state and heterozygous with other HEXB alterations in multiple unrelated individuals with Sandhoff disease (Ahn, 2010; Gort, 2012; Rattay, 2013; Gomez-Lira, 1995; Yamada, 2013; Kang, 2013; Grunseich, 2015; McInnes, 1992; Wakamatsu, 1992). This amino acid position is not well conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. - |
Sandhoff disease, adult form Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1995 | - - |
See cases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 29, 2019 | ACMG classification criteria: PM1, PM2, PP3, PP5 - |
Sandhoff disease, juvenile form Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
T;D
Vest4
MVP
MPC
0.20
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at