rs28942073

Variant names:

• chr5-74718804-C-T
• rs28942073
• NM_000521.4:c.1250C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BS1_Supporting

The NM_000521.4(HEXB):​c.1250C>T​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (3 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
HEXB	NM_000521.4	c.1250C>T	p.Pro417Leu	missense_variant	Exon 11 of 14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.575C>T	p.Pro192Leu	missense_variant	Exon 11 of 14		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.1250C>T	p.Pro417Leu	missense_variant	Exon 11 of 14	1	NM_000521.4	ENSP00000261416.7

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000589 AC: 148 AN: 251338 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000809 AC: 1182 AN: 1461788 Hom.: 3 Cov.: 32 AF XY: 0.000777 AC XY: 565 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00378

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000871

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74430

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000861 Hom.: 0

Bravo AF: 0.000461

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000659 AC: 80

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00166

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Pathogenic:11

Oct 25, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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). Invitae Evidence 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 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 1386607, 1531140). For these reasons, this variant has been classified as Pathogenic. -

Dec 31, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.‚Äã -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro417Leu variant in the HEXB gene has been previously reported in the homozygous or compound heterozygous state in several individuals with Sandhoff disease (McInnes et al., 1992; Wakamatsu et al.,1992; Gort et al., 2012; Yamada et al., 2013). This variant has also been identified in 127/129,062 European Non-Finnish chromosomes (159/282,736 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has been observed at a frequency low enough to be consistent with autosomal recessive carrier status. The p.Pro417Leu variant occurs near the splice junction of intron 10 and exon 11. Functional studies have demonstrated that this variant results in aberrant splicing due to activation of a cryptic splice site and exon 11 skipping (McInnes et al., 1992; Wakamatsu et al., 1992). Computational tools predict that the p.Pro417Leu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Pro417Leu variant as pathogenic for autosomal recessive Sandhoff disease based on the information above. [ACMG evidence codes used: PM3_Very Strong; PS3; PM2; PP3] -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Pathogenic:4

Nov 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP4, PM3_strong, PS3 -

Oct 21, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEXB: PM3:Very Strong, PM2 -

HEXB-related disorder Pathogenic:1

Jul 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

See cases Pathogenic:1

Apr 29, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM1, PM2, PP3, PP5 -

Sandhoff disease, juvenile form Pathogenic:1

Aug 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Benign	-0.083
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Pathogenic	0.92	D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.058	T;D
Vest4		0.71
MVP		0.95
MPC		0.20
ClinPred		0.20	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28942073; hg19: chr5-74014629; COSMIC: COSV54667890; COSMIC: COSV54667890;