Submissions for variant NM_001386140.1(MTTP):c.1618C>T (p.Arg540Cys)

gnomAD frequency: 0.00004  dbSNP: rs372321643

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042370	SCV001206048	pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 540 of the MTTP protein (p.Arg540Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with abetalipoproteinemia (PMID: 25108285, 27578136). 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: 840396). 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: 25108285). 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: 8939939, 10679949, 30522860). 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	RCV001275665	SCV002500299	likely pathogenic	Abetalipoproteinaemia	2022-03-10	criteria provided, single submitter	clinical testing	Variant summary: MTTP c.1618C>T (p.Arg540Cys) results in a non-conservative amino acid change located in the Vitellogenin, N-terminal domain (IPR001747) of the encoded protein sequence. 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 2.8e-05 in 251142 control chromosomes (gnomAD). c.1618C>T has been reported in the literature in individuals affected with Abetalipoproteinaemia (Bassen-Kornzweig Syndrome) (e.g. Miller_2014, Paquette_2016). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the lipid-transfer activity of the variant to be significantly reduced compared to wild-type (Miller_2014). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001275665	SCV001460967	likely pathogenic	Abetalipoproteinaemia	2020-09-16	no assertion criteria provided	clinical testing
New York Genome Center	RCV001275665	SCV003925356	uncertain significance	Abetalipoproteinaemia	2022-03-25	flagged submission	clinical testing