NM_000255.4:c.19C>T

Variant names:

• chr6-49459448-G-A
• rs761773115
• NM_000255.4:c.19C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000255.4(MMUT):​c.19C>T​(p.Gln7*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMUT NM_000255.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.22

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 69 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-49459448-G-A is Pathogenic according to our data. Variant chr6-49459448-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMUT	NM_000255.4	c.19C>T	p.Gln7*	stop_gained	Exon 2 of 13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.19C>T	p.Gln7*	stop_gained	Exon 2 of 13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.19C>T	p.Gln7*	stop_gained	Exon 2 of 13	1	NM_000255.4	ENSP00000274813.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250232 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln7*) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs761773115, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria (PMID: 15643616, 17957493). ClinVar contains an entry for this variant (Variation ID: 218984). For these reasons, this variant has been classified as Pathogenic. -

Methylmalonic acidemia Pathogenic:1

Feb 06, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUT c.19C>T (p.Gln7X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250232 control chromosomes. c.19C>T has been reported in the literature in individuals affected with Methylmalonic Acidemia and has been subsequently cited by others (example, Acquaviva_2005, Merinero_2008, Froese_2010, Imtiaz_2016, Chu_2016). One submitter (Gene Reviews) has provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

mut(0) enzymatic subtype when homozygous -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.22	N
Vest4		0.35
GERP RS		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs761773115; hg19: chr6-49427161; COSMIC: COSV51273370; COSMIC: COSV51273370;