rs564069299

chr6-49451692-C-T

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.1106G>A(p.Arg369His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging 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. R369C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.91

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 chr6-49451693-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 6-49451692-C-T is Pathogenic according to our data. 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. Variant chr6-49451692-C-T is described in Lovd as [Pathogenic]. Variant chr6-49451692-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMUT	NM_000255.4	c.1106G>A	p.Arg369His	missense_variant	6/13	ENST00000274813.4
MMUT	XM_005249143.4	c.1106G>A	p.Arg369His	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMUT	ENST00000274813.4	c.1106G>A	p.Arg369His	missense_variant	6/13	1	NM_000255.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250696 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74270

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000684 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 369 of the MUT protein (p.Arg369His). This variant is present in population databases (rs564069299, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 9929975, 16281286, 16490061, 17075691, 17113806, 22614770, 27167370, 27751223). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203846). 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%. Experimental studies have shown that this missense change affects MUT function (PMID: 25125334). This variant disrupts the p.Arg369 amino acid residue in MUT. Other variant(s) that disrupt this residue have been determined to be pathogenic (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	Mar 21, 2017	The R369H missense change in the MUT gene has been reported previously in association with methylmalonic acidemia (Janata et al. 1997; Lempp et al. 2007; Han et al. 2015). Expression studies found that R369H is associated with 1.3% methylmalonyl-CoA mutase activity compared to wild type (Forny et al. 2014). The R369H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret R369H to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 08, 2018	- -

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

Mar 29, 2019

Variant summary: MUT c.1106G>A (p.Arg369His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha/beta 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 6.2e-05 in 276352 control chromosomes (gnomAD). The variant, c.1106G>A, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Mikami_1999, Sakamoto_2007, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. In vitro studies indicate that this variant is associated with 1.3% of MUT activity compared to WT (Forny_2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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	0.86
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		1.0
MVP		1.0
MPC		0.54
ClinPred		0.98	D
GERP RS		5.0
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs564069299; hg19: chr6-49419405; COSMIC: COSV51275106;