VCV000066984.13 - ClinVar

NM_005334.3(HCFC1):c.344C>T (p.Ala115Val)

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.

(5)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005334.3(HCFC1):c.344C>T (p.Ala115Val)

Variation ID: 66984 Accession: VCV000066984.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 153964283 (GRCh38) [ NCBI UCSC ] X: 153229734 (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	Feb 14, 2024	Feb 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005334.3:c.344C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005325.2:p.Ala115Val	missense
NM_001410705.1:c.344C>T	NP_001397634.1:p.Ala115Val	missense
NM_005334.2:c.344C>T
NC_000023.11:g.153964283G>A
NC_000023.10:g.153229734G>A
NG_012513.1:g.12086C>T
NG_012513.2:g.12535C>T

... more HGVS ... less HGVS

Protein change

A115V

Other names

p.A115V

Canonical SPDI

NC_000023.11:153964282:G:A

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

loss_of_function_variant; Sequence Ontology [ SO:0002054]

RNAseq showed decreased expression of genes whose expression is controlled by HCFC1. [submitted by Undiagnosed Diseases Network, NIH]

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.

Links

ClinGen: CA144900 OMIM: 300019.0003 dbSNP: rs397515485 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.
HCFC1		-	-	GRCh38 GRCh37	1265	1566

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 cblX	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 16, 2023	RCV000057506.35
Disorders of Intracellular Cobalamin Metabolism	not provided (1)	no classification provided	-	RCV002513743.1

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.
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic acidemia with homocystinuria, type cblX Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003836367.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Methylmalonic acidemia with homocystinuria, type cblX Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001584879.4 First in ClinVar: Mar 23, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 24011988‚ 28363510‚ 28449119 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the HCFC1 protein (p.Ala115Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the HCFC1 protein (p.Ala115Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cobalamin X deficiency (PMID: 24011988, 28363510). ClinVar contains an entry for this variant (Variation ID: 66984). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HCFC1 function (PMID: 28449119). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic acidemia with homocystinuria, type cblX (X-linked inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002523183.1 First in ClinVar: Jun 10, 2022 Last updated: Jun 10, 2022	Publications: PubMed (4) PubMed: 28363510‚ 24011988‚ 28449119‚ 35013307 Number of individuals with the variant: 1 Clinical Features: Jaundice (present) , Abnormal delivery (present) , Primary Caesarian section (present) , Recurrent urinary tract infections (present) , Diverticulum of bladder (present) , Severely reduced … (more) Jaundice (present) , Abnormal delivery (present) , Primary Caesarian section (present) , Recurrent urinary tract infections (present) , Diverticulum of bladder (present) , Severely reduced visual acuity (present) , Seizure (present) , Generalized hypotonia (present) , Hyperhomocystinemia (present) , Gastrointestinal dysmotility (present) , Methylmalonic acidemia (present) , Abnormal circulating glycine concentration (present) , Severe global developmental delay (present) , Increased mean platelet volume (present) , Encephalomalacia (present) , Epileptic encephalopathy (present) (less) Age: 0-9 years Sex: male
Pathogenic (Sep 05, 2013)	no assertion criteria provided Method: literature only	METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblX TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000088618.4 First in ClinVar: Oct 20, 2013 Last updated: Dec 25, 2021	Publications: PubMed (1) PubMed: 24011988 Comment on evidence: In 9 unrelated males with methylmalonic aciduria and homocystinuria, cblX type (MAHCX; 309541), Yu et al. (2013) identified a hemizygous c.344C-T transition in exon 3 … (more) In 9 unrelated males with methylmalonic aciduria and homocystinuria, cblX type (MAHCX; 309541), Yu et al. (2013) identified a hemizygous c.344C-T transition in exon 3 of the HCFC1 gene, resulting in an ala115-to-val (A115V) substitution at a highly conserved residue in the second kelch motif. The mutation in the first patient was found by exome sequencing and confirmed by Sanger sequencing; the mutation was present in his unaffected mother. The variant was not found in the dbSNP, NHLBI Exome Variant Server, or 1000 Genomes Project databases. Sanger sequencing did not find the variant in 50 control individuals of European descent, but it was found in 1 female individual among 50 control individuals of African American descent. The patients had severely delayed psychomotor development apparent in infancy and intractable seizures associated in most cases with increased plasma homocysteine and increased serum methylmalonic acid. (less)
not provided (-)	no classification provided Method: literature only	Disorders of Intracellular Cobalamin Metabolism Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV003354491.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 24011988 Bookshelf: NBK1328 Bookshelf: NBK1328

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the HCFC1 protein (p.Ala115Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cobalamin X deficiency (PMID: 24011988, 28363510). ClinVar contains an entry for this variant (Variation ID: 66984). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HCFC1 function (PMID: 28449119). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002523183.1	Publications PubMed (4) Comment: RNAseq showed decreased expression of genes whose expression is controlled by HCFC1.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.	Chern T	Nature communications	2022	PMID: 35013307
Disorders of Intracellular Cobalamin Metabolism.	Adam MP	-	2021	PMID: 20301503
Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities.	Quintana AM	Human molecular genetics	2017	PMID: 28449119
X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid.	Scalais E	Pediatric neurology	2017	PMID: 28363510
An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.	Yu HC	American journal of human genetics	2013	PMID: 24011988

Text-mined citations for rs397515485 ...

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_005334.3(HCFC1):c.344C>T (p.Ala115Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515485 ...