NM_005334.3(HCFC1):c.344C>T (p.Ala115Val) AND Mental retardation 3, X-linked

Clinical significance:Pathogenic (Last evaluated: Jun 30, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000057506.25

Allele description [Variation Report for NM_005334.3(HCFC1):c.344C>T (p.Ala115Val)]

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

Gene:
HCFC1:host cell factor C1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq28
Genomic location:
Preferred name:
NM_005334.3(HCFC1):c.344C>T (p.Ala115Val)
HGVS:
  • NC_000023.11:g.153964283G>A
  • NG_012513.1:g.12086C>T
  • NM_005334.3:c.344C>TMANE SELECT
  • NP_005325.2:p.Ala115Val
  • NC_000023.10:g.153229734G>A
Protein change:
A115V; ALA115VAL
Links:
OMIM: 300019.0003; dbSNP: rs397515485
NCBI 1000 Genomes Browser:
rs397515485
Molecular consequence:
  • NM_005334.3:c.344C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mental retardation 3, X-linked (MAHCX)
Synonyms:
METHYLMALONIC ACIDEMIA AND HOMOCYSTEINEMIA, cblX TYPE; INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 3
Identifiers:
MONDO: MONDO:0010657; MedGen: C0796208; Orphanet: 369962; OMIM: 309541

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000088618OMIMno assertion criteria providedPathogenic
(Sep 5, 2013)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001584879Invitaecriteria provided, single submitter
Pathogenic
(Jun 30, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.

Yu HC, Sloan JL, Scharer G, Brebner A, Quintana AM, Achilly NP, Manoli I, Coughlin CR 2nd, Geiger EA, Schneck U, Watkins D, Suormala T, Van Hove JL, Fowler B, Baumgartner MR, Rosenblatt DS, Venditti CP, Shaikh TH.

Am J Hum Genet. 2013 Sep 5;93(3):506-14. doi: 10.1016/j.ajhg.2013.07.022.

PubMed [citation]
PMID:
24011988
PMCID:
PMC3769968

X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid.

Scalais E, Osterheld E, Weitzel C, De Meirleir L, Mataigne F, Martens G, Shaikh TH, Coughlin CR 2nd, Yu HC, Swanson M, Friederich MW, Scharer G, Helbling D, Wendt-Andrae J, Van Hove JLK.

Pediatr Neurol. 2017 Jun;71:65-69. doi: 10.1016/j.pediatrneurol.2016.12.003. Epub 2017 Jan 7.

PubMed [citation]
PMID:
28363510
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000088618.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 9 unrelated males with methylmalonic acidemia and homocysteinemia, 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001584879.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces alanine with valine at codon 115 of the HCFC1 protein (p.Ala115Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with cobalamin X deficiency (PMID: 24011988, 28363510). ClinVar contains an entry for this variant (Variation ID: 66984). Experimental studies on zebrafish embryos have shown that this missense change has a detrimental effect on the proliferation and differentiation of neural precursors (PMID: 28449119). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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