NM_032756.4(HPDL):c.3G>C (p.Met1Ile) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 10, 2021
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:: RCV002543439.2

Allele description [Variation Report for NM_032756.4(HPDL):c.3G>C (p.Met1Ile)]

NM_032756.4(HPDL):c.3G>C (p.Met1Ile)

Genes:

HPDL:4-hydroxyphenylpyruvate dioxygenase like [Gene - OMIM - HGNC]
LOC129930439:ATAC-STARR-seq lymphoblastoid active region 964 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_032756.4(HPDL):c.3G>C (p.Met1Ile)

HGVS:

NC_000001.11:g.45327151G>C
NM_032756.2:c.3G>C
NM_032756.4:c.3G>CMANE SELECT
NP_116145.1:p.Met1Ile
NC_000001.10:g.45792823G>C
NM_032756.3:c.3G>C

Protein change:

M1I

Links:

dbSNP: rs777607274

NCBI 1000 Genomes Browser:

rs777607274

Molecular consequence:

NM_032756.4:c.3G>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_032756.4:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003553738	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003553738

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 10, 2021)

germline

clinical testing

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

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

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Wiessner M, Maroofian R, Ni MY, Pedroni A, Müller JS, Stucka R, Beetz C, Efthymiou S, Santorelli FM, Alfares AA, Zhu C, Uhrova Meszarosova A, Alehabib E, Bakhtiari S, Janecke AR, Otero MG, Chen JYH, Peterson JT, Strom TM, De Jonghe P, Deconinck T, De Ridder W, et al.

Brain. 2021 Jun 22;144(5):1422-1434. doi: 10.1093/brain/awab041. Erratum in: Brain. 2021 Sep 4;144(8):e70.

PubMed [citation]

PMID:: 33970200
PMCID:: PMC8219359

Details of each submission

From Ambry Genetics, SCV003553738.3

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

Description

The c.3G>C (p.M1?) alteration is located in exon 1 of the HPDL gene and results from a G to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on data from gnomAD, the C allele has an overall frequency of 0.003% (6/202,546) total alleles studied. The highest observed frequency was 0.03% (6/22,658) of South Asian alleles. This alteration has been reported homozygous in an infant with global developmental delay, upper and lower limb pyramidal signs, spasticity, weakness, contractures, seizures, encephalopathic episodes, and an abnormal brain MRI (Wiessner, 2021). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is 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: May 1, 2024

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