Submissions for variant NM_000520.6(HEXA):c.1183del (p.Asp395fs)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174718	SCV001337992	likely pathogenic	Tay-Sachs disease	2023-02-22	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1183delG (p.Asp395IlefsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes. c.1183delG has been reported in the literature in an individual who was undergoing a Tay-Sachs carrier screening program (Tomczak_1994). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001174718	SCV003484575	pathogenic	Tay-Sachs disease	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp395Ilefs*4) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs770303210, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. ClinVar contains an entry for this variant (Variation ID: 917630). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV001174718	SCV002085676	likely pathogenic	Tay-Sachs disease	2020-04-01	no assertion criteria provided	clinical testing

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