ClinVar Miner

Submissions for variant NM_005957.4(MTHFR):c.1129C>T (p.Arg377Cys) (rs121434296)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000642247 SCV000763906 likely pathogenic Homocysteinemia due to MTHFR deficiency 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 377 of the MTHFR protein (p.Arg377Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121434296, ExAC 0.004%). This variant has been reported as a common variant in individuals affected with severe MTHFR deficiency in the Amish population. It has been identified as homozygous or in combination with other MTHFR variants in several individuals with severe MTHFR deficiency (PMID: 26872964, 12673793, 8940272, 25736335, 17409006, 26025547). This variant is also known as C1141T in the literature. ClinVar contains an entry for this variant (Variation ID: 3528). Experimental studies have shown that this missense change retains a significant amount of enzyme function in vitro, ranging from approximately from 50% to 100% of wild-type (PMID: 27743313, 10551815). This variant disrupts the p.Arg377 amino acid residue in MTHFR. Another variant that disrupts this residue has been observed in affected individuals (PMID: 24797679, 25736335), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756357 SCV000884147 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing The c.1129C>T; p.Arg377Cys variant has been reported multiple times in the literature. An African-American/Caucasian female with lethargy and failure to thrive at one month of age, and seizures, apnea, and hypotonia at three months of age was reported to be compound heterozygous for this variant as well as p.Leu323Pro (Goyette 1996). A 13-year-old male with developmental delay was reported to be compound heterozygous for the p.Arg377Cys and p.Met338Thr variants (Sibani 2003), and a study of families diagnosed with severe MTHFR deficiency reported two further individuals heterozygous for p.Arg377Cys and either p.His181Asp or p.Cys193Tyr (Tonetti 2003). A study of an Amish community found four children homozygous for the p.Arg377Cys variant, all of whom had slow head growth and arrested development in the first few months of life; while 68 heterozygotes were among 230 healthy individuals in the community, for an estimated population carrier frequency of 30% (Strauss 2007). The four p.Arg377Cys homozygotes all displayed elevated plasma N-homocysteinylated protein, Hcy-thiolactone and total homocysteine concentrations (Jakubowski 2008). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% (identified on 5 out of 126,714 chromosomes) and an East Asian population frequency of zero (out of 18,870 chromosomes), while the Exome Sequencing Project reports the variant frequency as 0.008% (identified on 1 out of 13,005 chromosomes). However, a study of congenital heart disease risk in China identified the p.Arg377Cys variant in a homozygous state in 12 healthy individuals and 27 affected patients among 467 studied Chinese Han individuals, with an allele frequency of over 25% (Zhang 2014). The discrepancy between this report and those of the population databases has not yet been explained. Although these findings are suggestive, based on the available evidence, the clinical significance of the p.Arg377Cys variant cannot be determined with certainty.
OMIM RCV000003706 SCV000023869 pathogenic Homocystinuria due to MTHFR deficiency 2007-06-01 no assertion criteria provided literature only

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