VCV000037319.6 - ClinVar

NM_005050.4(ABCD4):c.956A>G (p.Tyr319Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005050.4(ABCD4):c.956A>G (p.Tyr319Cys)

Variation ID: 37319 Accession: VCV000037319.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.3 14: 74292623 (GRCh38) [ NCBI UCSC ] 14: 74759326 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 31, 2013	Jul 18, 2022	May 26, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_005050.4:c.956A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005041.1:p.Tyr319Cys	missense
NM_001353591.2:c.830A>G	NP_001340520.1:p.Tyr277Cys	missense
NM_001353592.2:c.830A>G	NP_001340521.1:p.Tyr277Cys	missense
NM_001353593.2:c.695A>G	NP_001340522.1:p.Tyr232Cys	missense
NM_001353594.2:c.644A>G	NP_001340523.1:p.Tyr215Cys	missense
NM_001353595.2:c.542A>G	NP_001340524.1:p.Tyr181Cys	missense
NM_001353596.2:c.542A>G	NP_001340525.1:p.Tyr181Cys	missense
NM_001353597.2:c.491A>G	NP_001340526.1:p.Tyr164Cys	missense
NM_001353598.2:c.479A>G	NP_001340527.1:p.Tyr160Cys	missense
NM_001353599.2:c.479A>G	NP_001340528.1:p.Tyr160Cys	missense
NM_001353600.2:c.479A>G	NP_001340529.1:p.Tyr160Cys	missense
NM_001353601.2:c.479A>G	NP_001340530.1:p.Tyr160Cys	missense
NM_001353602.2:c.167A>G	NP_001340531.1:p.Tyr56Cys	missense
NM_001353603.2:c.167A>G	NP_001340532.1:p.Tyr56Cys	missense
NM_001353604.2:c.167A>G	NP_001340533.1:p.Tyr56Cys	missense
NM_001353605.2:c.167A>G	NP_001340534.1:p.Tyr56Cys	missense
NM_001353606.2:c.167A>G	NP_001340535.1:p.Tyr56Cys	missense
NM_001353607.2:c.167A>G	NP_001340536.1:p.Tyr56Cys	missense
NM_001353608.2:c.167A>G	NP_001340537.1:p.Tyr56Cys	missense
NM_001353609.2:c.167A>G	NP_001340538.1:p.Tyr56Cys	missense
NM_001353610.2:c.167A>G	NP_001340539.1:p.Tyr56Cys	missense
NM_020324.3:c.479A>G	NP_064720.1:p.Tyr160Cys	missense
NM_020325.3:c.956A>G	NP_064730.1:p.Tyr319Cys	missense
NR_003256.3:n.850A>G		non-coding transcript variant
NR_148466.2:n.878A>G		non-coding transcript variant
NR_148467.2:n.659A>G		non-coding transcript variant
NR_148468.2:n.636A>G		non-coding transcript variant
NR_148469.2:n.883A>G		non-coding transcript variant
NR_148470.2:n.845A>G		non-coding transcript variant
NR_148471.2:n.883A>G		non-coding transcript variant
NR_148472.2:n.932A>G		non-coding transcript variant
NR_148473.2:n.859A>G		non-coding transcript variant
NR_148474.2:n.978A>G		non-coding transcript variant
NC_000014.9:g.74292623T>C
NC_000014.8:g.74759326T>C
NG_032875.1:g.15442A>G
	O14678:p.Tyr319Cys

... more HGVS ... less HGVS

Protein change

Y319C, Y160C, Y164C, Y215C, Y232C, Y181C, Y277C, Y56C

Other names

Canonical SPDI

NC_000014.9:74292622:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

Links

ClinGen: CA130166 UniProtKB: O14678#VAR_069097 UniProtKB/Swiss-Prot: VAR_069097 OMIM: 603214.0001 dbSNP: rs201777056 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCD4		-	-	GRCh38 GRCh37	429	451

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Methylmalonic acidemia with homocystinuria, type cblJ	Uncertain significance (2)	criteria provided, single submitter	Aug 26, 2021	RCV000030859.10
not provided	not provided (1)	no classification provided	-	RCV000059785.1
Cobalamin C disease	Likely pathogenic (1)	criteria provided, single submitter	May 26, 2022	RCV002265570.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 26, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Methylmalonic acidemia with homocystinuria, type cblJ Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001389587.3 First in ClinVar: Jul 16, 2020 Last updated: May 16, 2022
Likely pathogenic (May 26, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002548357.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Publications: PubMed (2) PubMed: 33845046‚ 22922874 Comment: Variant summary: ABCD4 c.956A>G (p.Tyr319Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: ABCD4 c.956A>G (p.Tyr319Cys) results in a non-conservative amino acid change in 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 3.6e-05 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.956A>G has been reported in the literature in the compound heterozygous state in an individual who was affected with Methylmalonic Acidemia With Homocystinuria (Coelho_2012). In vitro experiments suggest that the variant does not impact protein localization, but that ATPase and cobalamin transport activities are lost compared to the wild-type ABCD4 protein (Kitai_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Oct 01, 2012)	no assertion criteria provided Method: literature only	METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblJ TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000053534.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 12, 2021	Publications: PubMed (1) PubMed: 22922874 Comment on evidence: In a North American child with methylmalonic aciduria and homocystinuria of complementation group J (MAHCJ; 614857), Coelho et al. (2012) identified compound heterozygosity for 2 … (more) In a North American child with methylmalonic aciduria and homocystinuria of complementation group J (MAHCJ; 614857), Coelho et al. (2012) identified compound heterozygosity for 2 mutations in the ABCD4 gene: a 956A-G transition resulting in a tyr319-to-cys (Y319C) substitution in the last transmembrane domain, and a 2-bp insertion (1746insCT; 603214.0001), resulting in a frameshift and premature termination (Glu583LeufsTer9) leading to the removal of 14 residues from the C terminus in the predicted cytosolic nucleotide binding domain. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for one of the mutations. Neither mutation was found in the 1000 Genomes Project database. Expression of wildtype ABCD4 in patient fibroblasts led to rescue of the biochemical phenotype. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	UniProtKB/Swiss-Prot Accession: SCV000091355.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013

Comment:

Variant summary: ABCD4 c.956A>G (p.Tyr319Cys) results in a non-conservative amino acid change in 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 3.6e-05 in 251364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.956A>G has been reported in the literature in the compound heterozygous state in an individual who was affected with Methylmalonic Acidemia With Homocystinuria (Coelho_2012). In vitro experiments suggest that the variant does not impact protein localization, but that ATPase and cobalamin transport activities are lost compared to the wild-type ABCD4 protein (Kitai_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The lysosomal protein ABCD4 can transport vitamin B(12) across liposomal membranes in vitro.	Kitai K	The Journal of biological chemistry	2021	PMID: 33845046
Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism.	Coelho D	Nature genetics	2012	PMID: 22922874

Text-mined citations for rs201777056 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005050.4(ABCD4):c.956A>G (p.Tyr319Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201777056 ...