NM_080669.6(SLC46A1):c.3G>A (p.Met1Ile) AND Cobalamin C disease

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Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 14, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004544220.1

Allele description

NM_080669.6(SLC46A1):c.3G>A (p.Met1Ile)

Genes:

LOC130060550:ATAC-STARR-seq lymphoblastoid silent region 8340 [Gene]
SLC46A1:solute carrier family 46 member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q11.2

Genomic location:

Preferred name:

NM_080669.6(SLC46A1):c.3G>A (p.Met1Ile)

HGVS:

NC_000017.11:g.28406112C>T
NG_013306.1:g.5099G>A
NG_195853.1:g.159C>T
NM_001242366.3:c.3G>A
NM_080669.6:c.3G>AMANE SELECT
NP_001229295.1:p.Met1Ile
NP_542400.2:p.Met1Ile
NP_542400.2:p.Met1Ile
LRG_183t1:c.3G>A
LRG_183:g.5099G>A
LRG_183p1:p.Met1Ile
NC_000017.10:g.26733130C>T
NM_080669.3:c.3G>A

Protein change:

M1I

Molecular consequence:

NM_001242366.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_080669.6:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001242366.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_080669.6:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cobalamin C disease
Synonyms:: Cobalamin-C methylmalonic acidemia and homocystinuria; Methylmalonic acidemia and homocystinuria cblC type; Methylmalonic aciduria and homocystinuria, Vitamin B12-responsive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010184; MedGen: C1848561; Orphanet: 26; Orphanet: 79282; OMIM: 277400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005040782	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 14, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24534056, 21602279 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005040782

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 14, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The first Chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1.

Wang Q, Li X, Ding Y, Liu Y, Qin Y, Yang Y.

Brain Dev. 2015 Jan;37(1):163-7. doi: 10.1016/j.braindev.2014.01.010. Epub 2014 Feb 15.

PubMed [citation]

PMID:: 24534056

Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function.

Zhao R, Shin DS, Diop-Bove N, Ovits CG, Goldman ID.

J Biol Chem. 2011 Jul 8;286(27):24150-8. doi: 10.1074/jbc.M111.236539. Epub 2011 May 20.

PubMed [citation]

PMID:: 21602279
PMCID:: PMC3129196

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040782.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: MMACHC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246258 control chromosomes (gnomAD). c.3G>A has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Lerner-Ellis_2006, Nogueira_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 7, 2024

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