6-49435558-GAG-CAC

Variant names:

• chr6-49435558-GAG-CAC
• NM_000255.4:c.2020_2022delCTCinsGTG
• MMUT p.Leu674Val

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM1 PM5 PP2 PP3

The NM_000255.4(MMUT):​c.2020_2022delCTCinsGTG​(p.Leu674Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L674F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

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]

MMUT Gene-Disease associations (from GenCC):

• methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• vitamin B12-unresponsive methylmalonic acidemia type mut-

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• vitamin B12-unresponsive methylmalonic acidemia type mut0

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_000255.4 (MMUT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000255.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-49435560-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 583274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 150 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.22855 (below the threshold of 3.09). Trascript score misZ: 1.0842 (below the threshold of 3.09). GenCC associations: The gene is linked to methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, vitamin B12-unresponsive methylmalonic acidemia type mut-, vitamin B12-unresponsive methylmalonic acidemia type mut0.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	NM_000255.4	MANE Select	c.2020_2022delCTCinsGTG	p.Leu674Val	missense	N/A	NP_000246.2	P22033

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.2020_2022delCTCinsGTG	p.Leu674Val	missense	N/A	ENSP00000274813.3	P22033
	MMUT	ENST00000878060.1		c.2020_2022delCTCinsGTG	p.Leu674Val	missense	N/A	ENSP00000548119.1
	MMUT	ENST00000878062.1		c.2020_2022delCTCinsGTG	p.Leu674Val	missense	N/A	ENSP00000548121.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-49403271;