rs121907985
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000521.4(HEXB):c.1510C>T(p.Pro504Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P504P) has been classified as Likely benign.
Frequency
Consequence
NM_000521.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXB | NM_000521.4 | c.1510C>T | p.Pro504Ser | missense_variant, splice_region_variant | 13/14 | ENST00000261416.12 | |
HEXB | NM_001292004.2 | c.835C>T | p.Pro279Ser | missense_variant, splice_region_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXB | ENST00000261416.12 | c.1510C>T | p.Pro504Ser | missense_variant, splice_region_variant | 13/14 | 1 | NM_000521.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251200Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135754
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461534Hom.: 0 Cov.: 30 AF XY: 0.0000316 AC XY: 23AN XY: 727114
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
ClinVar
Submissions by phenotype
Sandhoff disease Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The HEXB c.1510C>T (p.Pro504Ser) variant was identified in the compound heterozygous state with the c.171delG (p.Trp57Cysfs7) variant in 1 individual with a history of muscle weakness and fasciculations in upper and lower limbs, and were confirmed to be in trans via sanger sequencing and segregation analysis (PMID: 34210542). The variant was also identified in the heterozygous state in two French Canadian sisters with Sandhoff disease alongside a 16-kb HEXB deletion on the other other allele (PMID: 9694901). The HEXB c.1510C>T has been previously reported to be associated with Sandhoff disease, as the variant decreases rate of heterodimer transport by approximately 45%, lowers heat stability, and impacts the ability of HEX A to hydrolyze its natural substrates (PMID: 9694901). The HEXB c.1510C>T (p.Pro504Ser) variant was identified in ClinVar (classified as likely pathogenic by Invitae, Natera Inc, and Women's Health and Genetics/Laboratory Corporation of America, LabCorp) and dbSNP (ID: rs121907985), but not COSMIC databases. The variant was identified in control databases in 10 of 282586 chromosomes (0 homozygous) at a frequency of 0.00003539, and was observed at the highest frequency in the Latino/Admixed American population in 8 of 35420 chromosomes (freq: 0.0002259) (Genome Aggregation Database November 15, 2022, v2.1.1). The p.Pro504 residue is conserved and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in-silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 504 of the HEXB protein (p.Pro504Ser). This variant is present in population databases (rs121907985, gnomAD 0.02%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 9694901, 34210542). 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. ClinVar contains an entry for this variant (Variation ID: 3884). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HEXB function (PMID: 9694901, 23127958). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 21, 2022 | Variant summary: HEXB c.1510C>T (p.Pro504Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 251200 control chromosomes. c.1510C>T has been reported in the literature as compound heterozygous genotypes in individuals affected with Sandhoff Disease (example, Hou_1998, Maegawa_2006, Tropak_2004, Alomso-Perez_2021, Masingue_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hou_1998). The most pronounced variant effect results in decreased level of heterodimer transport out of the endoplasmic reticulum by approx 45%, lowered heat stability, lowered ratio of units of ganglioside/ units of artificial substrate hydrolyzed, affects the ability of Hex A to hydrolyze its natural but not its artificial substrates. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 09, 2020 | - - |
Sandhoff disease, chronic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 14, 1998 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at