Submissions for variant NM_001386140.1(MTTP):c.2593G>T (p.Gly865Ter)

gnomAD frequency: 0.00004  dbSNP: rs146064714

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015311	SCV000696301	pathogenic	Abetalipoproteinaemia	2017-06-19	criteria provided, single submitter	clinical testing	Variant summary: The MTTP c.2593G>T (p.Gly865X) variant results in a premature termination codon, predicted to cause a truncated or absent MTTP protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 11/122676 control chromosomes at a frequency of 0.0000897, which does not exceed the estimated maximal expected allele frequency of a pathogenic MTTP variant (0.0010607). In the Gnomad control database which has additional ethnic subgroups, almost all carriers for this variant were of Ashkenazi Jewish origin, which supports literature evidence that this variant may be an AJ founder mutation (Benayoun_2007). The variant has been reported in numerous individuals in the literature in the homozygous state, and has been reported to result in the complete absence of MTP activity in in vitro studies and patient intestinal biopsy samples (Ricci_1995). Taken together, this variant is classified as pathogenic.
Counsyl	RCV000015311	SCV000792926	pathogenic	Abetalipoproteinaemia	2017-07-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000760413	SCV000890290	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate disruption of the normal binding of the MTP protein with protein disulfide isomerase (PDI), indicating that the last 30 amino acid residues are required for the formation of the MTP-PDI complex (Ricci et al., 1995; Rehberg et al., 1996); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost; This variant is associated with the following publications: (PMID: 27415407, 8939939, 7782284, 25552696, 27271787, 23475612, 23556456, 10679949, 31589614, 32041611, 17275380, 20592474)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760413	SCV000940106	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly865*) in the MTTP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MTTP protein. This variant is present in population databases (rs146064714, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with MTTP-related conditions and abetalipoproteinaemia (PMID: 7782284, 8533758, 10679949, 17275380, 20592474, 27271787). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14243). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MTTP function (PMID: 7782284). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000015311	SCV000035570	pathogenic	Abetalipoproteinaemia	2007-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000015311	SCV001460972	pathogenic	Abetalipoproteinaemia	2020-09-16	no assertion criteria provided	clinical testing