Submissions for variant NM_000520.6(HEXA):c.972T>A (p.Val324=)

gnomAD frequency: 0.00001  dbSNP: rs28942072

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001781173	SCV002103528	likely pathogenic	Tay-Sachs disease	2022-12-22	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.972T>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5 prime splicing donor site in exon 8 located 17 base pairs upstream of the canonical intron 8 splice donor site. The variant was absent in 251352 control chromosomes (gnomAD). c.972T>A has been reported in the literature in a compound heterozygous individual affected with GM2-gangliosidosis (Wicklow_2004). Bioinformatics prediction of utilization of the alternate donor site was confirmed using cDNA from this affected individual and consisted both normal and short transcript (Wicklow_2004). Authors state that RT/PCR analyses confirmed the presence of low levels of abnormal transcript in proband fibroblasts that contained a premature stop codon in the mRNA at a position equivalent to amino acid 340, and therefore rapid decay of the transcript via NMD. Sequencing of this abnormal transcript revealed a 17 base pair deletion due to the usage of the novel upstream splice donor site in exon 8. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001781173	SCV003267898	uncertain significance	Tay-Sachs disease	2023-03-21	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 3943). This variant has been observed in individual(s) with hexosaminidase A deficiency (PMID: 15108204). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 324 of the HEXA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXA protein.
GeneDx	RCV003332074	SCV004039927	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and in silico splice prediction algorithms suggest a damaging effect resulting in aberrant splicing (Wicklow et al., 2004); This variant is associated with the following publications: (PMID: 35936646, 15108204)
OMIM	RCV000004149	SCV000024315	pathogenic	Gm2-gangliosidosis, subacute	2004-06-01	no assertion criteria provided	literature only