Submissions for variant NM_005957.5(MTHFR):c.1163G>A (p.Arg388His)

gnomAD frequency: 0.00002  dbSNP: rs769953411

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000661921	SCV000784244	likely pathogenic	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2018-03-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002263926	SCV002543865	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689830	SCV005186109	uncertain significance	not specified	2024-05-01	criteria provided, single submitter	clinical testing	Variant summary: MTHFR c.1163G>A (p.Arg388His) results in a non-conservative amino acid change in 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 2e-05 in 251490 control chromosomes. c.1163G>A has been reported in the literature at a compound heterozygous state with a second VUS missense in one individual affected with unspecified genetic disease (Capalbo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Homocystinuria Due To Methylene Tetrahydrofolate Reductase Deficiency. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Weile_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 34214447). ClinVar contains an entry for this variant (Variation ID: 548463). Based on the evidence outlined above, the variant was classified as VUS.