Submissions for variant NM_000521.4(HEXB):c.1627G>A (p.Ala543Thr)

gnomAD frequency: 0.00012  dbSNP: rs121907984

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079061	SCV000110930	other	not provided	2012-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079061	SCV000697176	likely benign	not provided	2016-10-31	criteria provided, single submitter	clinical testing	Variant summary: The HEXB c.1627G>A (p.Ala543Thr) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 115/120804 (1/1052, 1 homozygote), predominantly observed in the South Asian cohort, 92/16490 (1/179, 1 homozygote), which exceeds the estimated maximal expected allele frequency for a pathogenic HEXB variant of 1/676. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has been reported in multiple affected and healthy homozygous individuals via publications. Functional studies have shown that the variant of interest is a heat labile allele, meaning that it leads to reduction in enzyme activity and mightresult in a false non-TSD or non-SD diagnosis. Likewise, a doubly heterozygous person, for TSD and for HLB, could be misdiagnosed as a normal homozygote. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "benign," along with the reporting cautionary awareness for the heat labile aspect. Therefore, to indicate the potential for the variant to cause false negative results, a classification of "Probable Normal Variant/Likely Benign," has been assigned to this variant.
Invitae	RCV000987527	SCV001055645	likely benign	Sandhoff disease	2024-01-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000987527	SCV001136840	likely benign	Sandhoff disease	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987527	SCV001315843	likely benign	Sandhoff disease	2018-01-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000987527	SCV001440662	likely benign	Sandhoff disease	2019-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000004085	SCV000024251	benign	HEXOSAMINIDASE B, HEAT-LABILE POLYMORPHISM	1997-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000987527	SCV002084958	benign	Sandhoff disease	2020-01-09	no assertion criteria provided	clinical testing