rs772552898

Positions:

• chr6-49451693-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000255.4(MMUT):​c.1105C>T​(p.Arg369Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 10.0

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000255.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-49451692-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 203846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 6-49451693-G-A is Pathogenic according to our data. Variant chr6-49451693-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.1105C>T	p.Arg369Cys	missense_variant	6/13	ENST00000274813.4
MMUT	XM_005249143.4	c.1105C>T	p.Arg369Cys	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.1105C>T	p.Arg369Cys	missense_variant	6/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250668 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135498

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461472 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727048

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 09, 2020	The MMUT c.1105C>T; p.Arg369Cys variant (rs772552898) is reported in the literature in the compound heterozygous state with other pathogenic variants in multiple individuals affected with methylmalonic aciduria (Han 2015, Jung 2005, Nizon 2013, Sakamoto 2007, Worgan 2006). This variant is reported in ClinVar (Variation ID: 218989), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 369 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1106G>A; p.Arg369His) has been reported in individuals with methylmalonic aciduria and is considered pathogenic (Han 2015, Jung 2005, Sakamoto 2007, Worgan 2006). Based on available information, the p.Arg369Cys variant is considered to be pathogenic. References: Han LS et al. Clinical features and MUT gene mutation spectrum in Chinese patients with isolated methylmalonic acidemia: identification of ten novel allelic variants. World J Pediatr. 2015 Nov;11(4):358-65. Jung JW et al. Mutation analysis of the MCM gene in Korean patients with MMA. Mol Genet Metab. 2005 Apr;84(4):367-70. Epub 2004 Dec 19. Nizon M et al. Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J Rare Dis. 2013 Sep 23;8:148. Sakamoto O et al. Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia. J Hum Genet. 2007;52(1):48-55. Worgan LC et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. 2006 Jan;27(1):31-43. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 369 of the MUT protein (p.Arg369Cys). This variant is present in population databases (rs772552898, gnomAD 0.006%). This missense change has been observed in individuals with methylmalonic acidemia (PMID: 15781199, 16281286, 17075691). ClinVar contains an entry for this variant (Variation ID: 218989). 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 MUT protein function with a positive predictive value of 95%. This variant disrupts the p.Arg369 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16281286, 25125334, 27751223; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2016	The R369C missense variant in the MUT gene has been reported previously in multiple patients in association with methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (Jung et al. 2005; Ktena et al. 2015; Sakamoto et al. 2007; Merinero et al. 2008; Nizon et al. 2013). R369C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts R369C is probably damaging to the protein structure/function. Furthermore, a conservative amino acid substitution at the same position (R369H) appears to be a common variant in Japanese patients with MMA and is reported to be associated with 1% of wild-type enzyme activity (Sakamoto et al. 2007). Therefore, we interpret R369C to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 20, 2017	- -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Methylmalonic acidemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 30, 2021

Variant summary: MMUT (legacy gene name MUT) c.1105C>T (p.Arg369Cys) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain of 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 250668 control chromosomes. c.1105C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (example, Forny_2016, Jung_2004, Worgan_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in propionate incorporation and Methylmalonyl-CoA mutase enzyme activity values that were considerably lower than controls (example, Forny_2016, Worgan_2006). Multiple clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.0
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772552898; hg19: chr6-49419406; COSMIC: COSV99222325;