Submissions for variant NM_001386140.1(MTTP):c.1619G>A (p.Arg540His)

gnomAD frequency: 0.00004  dbSNP: rs199422220

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222493	SCV001394592	pathogenic	not provided	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 540 of the MTTP protein (p.Arg540His). This variant is present in population databases (rs199422220, gnomAD 0.003%). This missense change has been observed in individual(s) with abetalipoproteinemia (PMID: 8939939, 10679949, 30522860). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 14238). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTTP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MTTP function (PMID: 8939939, 23475612). This variant disrupts the p.Arg540 amino acid residue in MTTP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25108285, 27578136). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015306	SCV002765991	pathogenic	Abetalipoproteinaemia	2022-11-16	criteria provided, single submitter	clinical testing	Variant summary: MTTP c.1619G>A (p.Arg540His) results in a non-conservative amino acid change located in the Vitellogenin, N-terminal (IPR039988) of the encoded protein sequence, specifically within the alpha-helical region (Khatun_2013). Another missense variant affecting the same amino acid has been classified as likely pathogenic by our laboratory (c.1618C>T, p.Arg540Cys), providing moderate evidence of pathogenicity. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251154 control chromosomes. c.1619G>A has been reported in the literature in individuals affected with Abetalipoproteinaemia (Rehberg_1996, Wang_2000, Di Filippo_2019), with evidence of co-segregation in two families. Some individuals are reported as compound heterozygous, carrying other variants in trans likely to be pathogenic. These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function, showing R540H loses phospholipid and triglyceride transfer activities and the ability to support apoB secretion (Rehberg_1996, Khatun_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000015306	SCV000035565	pathogenic	Abetalipoproteinaemia	1996-11-22	no assertion criteria provided	literature only
GeneReviews	RCV000015306	SCV000902493	not provided	Abetalipoproteinaemia		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV001222493	SCV001979304	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001222493	SCV001979431	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000015306	SCV002082439	pathogenic	Abetalipoproteinaemia	2017-08-03	no assertion criteria provided	clinical testing