Submissions for variant NM_001386140.1(MTTP):c.2657C>T (p.Pro886Leu)

gnomAD frequency: 0.00028  dbSNP: rs144600401

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000601949	SCV000446734	uncertain significance	Abetalipoproteinaemia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000601949	SCV000745232	likely benign	Abetalipoproteinaemia	2017-06-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245458	SCV001418748	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 886 of the MTTP protein (p.Pro886Leu). This variant is present in population databases (rs144600401, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with MTTP-related conditions. ClinVar contains an entry for this variant (Variation ID: 347046). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Baylor Genetics	RCV000601949	SCV001520460	uncertain significance	Abetalipoproteinaemia	2019-08-06	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Pars Genome Lab	RCV000601949	SCV001652874	uncertain significance	Abetalipoproteinaemia	2021-05-18	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000601949	SCV003925411	uncertain significance	Abetalipoproteinaemia	2022-02-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021936	SCV005011472	uncertain significance	Inborn genetic diseases	2021-09-15	criteria provided, single submitter	clinical testing	The c.2657C>T (p.P886L) alteration is located in exon 19 (coding exon 18) of the MTTP gene. This alteration results from a C to T substitution at nucleotide position 2657, causing the proline (P) at amino acid position 886 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV001245458	SCV005410575	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	BP4
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000601949	SCV000734302	likely benign	Abetalipoproteinaemia		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001245458	SCV001920353	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000601949	SCV002082465	uncertain significance	Abetalipoproteinaemia	2020-01-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752870	SCV005361273	uncertain significance	MTTP-related disorder	2024-07-03	no assertion criteria provided	clinical testing	The MTTP c.2657C>T variant is predicted to result in the amino acid substitution p.Pro886Leu. This variant was reported in an individual with retinal / optic nerve disease (Table S12, Diñeiro et al 2020. PubMed ID: 32483926). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomA. This variant could be benign. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.