Submissions for variant NM_015702.3(MMADHC):c.746A>G (p.Tyr249Cys)

gnomAD frequency: 0.00001  dbSNP: rs118204046

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001378885	SCV001576573	likely pathogenic	Methylmalonic aciduria and homocystinuria type cblD	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 249 of the MMADHC protein (p.Tyr249Cys). This variant is present in population databases (rs118204046, gnomAD 0.04%). This missense change has been observed in individual(s) with cobalamin D deficiency (PMID: 18385497, 22156578, 25155779). ClinVar contains an entry for this variant (Variation ID: 763). 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 MMADHC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MMADHC function (PMID: 18385497, 22156578). 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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001378885	SCV002054028	pathogenic	Methylmalonic aciduria and homocystinuria type cblD		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844002	SCV002103909	pathogenic	Cobalamin C disease	2022-02-02	criteria provided, single submitter	clinical testing	Variant summary: MMADHC c.746A>G (p.Tyr249Cys) 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 7.2e-05 in 251290 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MMADHC causing Methylmalonic Acidemia With Homocystinuria (7.2e-05 vs 0.00079), allowing no conclusion about variant significance. c.746A>G has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia With Homocystinuria, including one heterozygote (Coelho_2008) and 3 homozygotes (Stucki_2012, Atkinson_2014). These data indicate that the variant is very likely to be associated with disease. Two publications have reported experimental evidence evaluating an impact on protein function, where the variant protein was found impacting methylcobalamin synthesis (with 10%-<30% of normal activity) but not adenosylcobalamin synthesis (Coelho_2008, Stucki_2012). One ClinVar submitter has assessed this variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251849	SCV002523332	uncertain significance	See cases	2019-03-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PP3, PP5
Genetics and Molecular Pathology, SA Pathology	RCV001378885	SCV002761653	pathogenic	Methylmalonic aciduria and homocystinuria type cblD	2022-03-25	criteria provided, single submitter	clinical testing	The MMADHC c.746A>G variant is classified as Pathogenic (PS4_Moderate, PS3, PM2, PM3, PP3) The MMADHC c.746A>G variant is a single nucleotide change in exon 8/8 of the MMADHC gene, which is predicted to change the amino acid tyrosine at position 249 in the protein to cysteine. The variant has been reported in probands with a clinical presentation of OMIM:277410 ( Detected in at least 4 affected individuals ) (PS4_Moderate). The variant is rare in population databases (PM2). Well-established functional studies show a deleterious effect of this variant (PS3). PubMed: 18385497 - Severely reduced methionine or methylcobalamin synthesis in either cblD-homocystinuria or cblD-combined cells. PMID: 22156578 - Expression studies showed that the c.746A>G;p.(Tyr249Cys) variant was unable to rescue methylcobalamin (MeCbl) synthesi. This variant has been detected in trans with a pathogenic variant c.545C>A;p.(T182N) for this recessive condition (PM3). + 3 homozygous occurrences. Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs118204046) and in the HGMD database: CM081190. It has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 763). - Variant detected in an individual with homocystinuria. Variant in trans with c.545C>A;p.(Thr182Asn). - Constructs containing the missense alleles associated with isolated homocystinuria (545C→A, 746A→G, and 776T→C) did not restore methionine or methylcobalamin synthesis in either cblD-homocystinuria or cblD-combined cells, confirming that these mutant alleles cause the homocystinuria phenotype.
Baylor Genetics	RCV001378885	SCV004193233	likely pathogenic	Methylmalonic aciduria and homocystinuria type cblD	2023-07-21	criteria provided, single submitter	clinical testing
OMIM	RCV000000799	SCV000020949	pathogenic	Homocystinuria, cblD type, variant 1	2008-04-03	no assertion criteria provided	literature only
Natera, Inc.	RCV001378885	SCV002083912	likely pathogenic	Methylmalonic aciduria and homocystinuria type cblD	2021-07-29	no assertion criteria provided	clinical testing