Submissions for variant NM_000520.6(HEXA):c.778C>T (p.Pro260Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155632	SCV003844347	likely pathogenic	Tay-Sachs disease	2023-02-05	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.778C>T (p.Pro260Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence (ACMG PM1). Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant was absent in 251482 control chromosomes (ACMG PM2). c.778C>T has been reported in the literature as a biallelic compound heterozygous or homozygous genotype in at-least two individuals affected with Tay-Sachs Disease (ACMG PP4, example, Gort_2012, Monies_2019). The compound heterozygous genotype was reported in a juvenile-adult presentation (Gort_2012) while the homozygous genotype was reported in an infantile onset presentation (Monies_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV004719314	SCV005326044	uncertain significance	not provided	2024-01-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31367523, 32815230, 31130284, 22789865)