chr6-49441858-A-C

Variant names:

• chr6-49441858-A-C
• rs1554158951
• NM_000255.4:c.1790T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000255.4(MMUT):​c.1790T>G​(p.Ile597Arg) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 8.95
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 vitamin B12-unresponsive methylmalonic acidemia type mut-, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, vitamin B12-unresponsive methylmalonic acidemia type mut0.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	NM_000255.4	MANE Select	c.1790T>G	p.Ile597Arg	missense	Exon 10 of 13	NP_000246.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMUT	ENST00000274813.4	TSL:1 MANE Select	c.1790T>G	p.Ile597Arg	missense	Exon 10 of 13	ENSP00000274813.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUT c.1790T>G (p.Ile597Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes (GNOMad). c.1790T>G has been reported in the literature in at least one compound heterozygous individual affected with Methylmalonic Acidemia, who also carried a second pathogenic variant (Han_2015, Han_2017, Yu_2021, Liang_2023). These data do not allow clear conclusions about variant significance. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated that the variant did not affect protein expression, but decreased its activity, resulting in about 20% of normal (Han_2017). The following publications have been ascertained in the context of this evaluation (PMID: 26454439, 28101778, 34668645, 37316190). ClinVar contains an entry for this variant (Variation ID: 551764). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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

May 15, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.94	D
PhyloP100		8.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.023	D
Sift4G	Benign	0.079	T
Vest4		0.96
MutPred		0.64		Gain of disorder (P = 0.0257)
MVP		1.0
MPC		0.47
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.94
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs1554158951; hg19: chr6-49409571;