Submissions for variant NM_005957.5(MTHFR):c.667G>A (p.Asp223Asn)

gnomAD frequency: 0.00068  dbSNP: rs150847674

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595772	SCV000705391	uncertain significance	not provided	2017-02-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082026	SCV001005760	likely benign	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000595772	SCV002028275	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	Reported in a patient with moderate hyperhomocysteinaemia who harbored another MTHFR variant; however, segregation information was not provided and the phase of the variants is unknown (PMID: 17457696); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate folate remedial behavior (PMID: 18523009, 34214447); This variant is associated with the following publications: (PMID: 19447376, 20847280, 34214447, 33671795, 18523009, 17457696)
Revvity Omics, Revvity	RCV001082026	SCV004236392	uncertain significance	Homocystinuria due to methylene tetrahydrofolate reductase deficiency	2023-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701685	SCV005204424	likely benign	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: MTHFR c.667G>A (p.Asp223Asn) results in a conservative amino acid change in 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 0.00014 in 1613248 control chromosomes, predominantly at a frequency of 0.0025 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in MTHFR-related homocystinuria. c.667G>A has been reported in the literature in at least one individual with moderate hyperhomocysteinaemia in an asymptomatic individual who also carried the c.665C>T polymorphism in the compound heterozygous state (e.g. Rummel_2007). These report(s) do not provide unequivocal conclusions about association of the variant with MTHFR-related homocystinuria. In vitro experimental studies in yeast were inclunclusive regarding the pathogenicity of this variant (e.g. Marini_2008, Weile_2021). This variant is also known as c.883G>A(p.D291N). The following publications have been ascertained in the context of this evaluation (PMID: 18523009, 17457696, 34214447). ClinVar contains an entry for this variant (Variation ID: 499744). Based on the evidence outlined above, the variant was classified as likely benign.