Submissions for variant NM_001386140.1(MTTP):c.1981G>A (p.Gly661Ser)

gnomAD frequency: 0.02355  dbSNP: rs113337987

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000625116	SCV000446727	benign	Abetalipoproteinaemia	2018-01-12	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625116	SCV000743813	benign	Abetalipoproteinaemia	2015-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175049	SCV001338586	likely benign	not specified	2020-04-13	criteria provided, single submitter	clinical testing	Variant summary: MTTP c.1981G>A (p.Gly661Ser) results in a non-conservative amino acid change located in the Lipid transport protein, N-terminal domain (IPR001747) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.027 in 250916 control chromosomes in the gnomAD database, including 252 homozygotes. The observed variant frequency is approximately 25-fold the estimated maximal expected allele frequency for a pathogenic variant in MTTP causing Abetalipoproteinaemia (Bassen-Kornzweig Syndrome) phenotype (0.0011), strongly suggesting that the variant is benign. c.1981G>A has been reported in the literature in individuals affected with Abetalipoproteinaemia (Bassen-Kornzweig Syndrome; e.g. Vongsuvanh_2007) and FHBL (homozygous familial hypobetalipoproteinaemia; e.g. Walsh_2016). These reports do not provide unequivocal conclusions about association of the variant with Abetalipoproteinaemia (Bassen-Kornzweig Syndrome). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Walsh_2016). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV001510429	SCV001717461	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000625116	SCV001737294	benign	Abetalipoproteinaemia	2021-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001510429	SCV001780583	likely benign	not provided	2020-10-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33111339)
Clinical Genetics, Academic Medical Center	RCV001175049	SCV001921926	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000625116	SCV002082451	benign	Abetalipoproteinaemia	2019-10-28	no assertion criteria provided	clinical testing