NM_000155.4(GALT):c.290A>G (p.Asn97Ser) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 6, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000022077.9

Allele description [Variation Report for NM_000155.4(GALT):c.290A>G (p.Asn97Ser)]

NM_000155.4(GALT):c.290A>G (p.Asn97Ser)

Gene:
GALT:galactose-1-phosphate uridylyltransferase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9p13.3
Genomic location:
Preferred name:
NM_000155.4(GALT):c.290A>G (p.Asn97Ser)
HGVS:
  • NC_000009.12:g.34647529A>G
  • NG_009029.2:g.5941A>G
  • NG_028966.1:g.345A>G
  • NM_000155.4:c.290A>GMANE SELECT
  • NM_001258332.2:c.50+271A>G
  • NP_000146.2:p.Asn97Ser
  • NC_000009.11:g.34647526A>G
  • NM_000155.3:c.290A>G
  • P07902:p.Asn97Ser
Links:
UniProtKB: P07902#VAR_002559; dbSNP: rs111033669
NCBI 1000 Genomes Browser:
rs111033669
Molecular consequence:
  • NM_001258332.2:c.50+271A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000155.4:c.290A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (GALAC1)
Synonyms:
GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; Galactose-1-phosphate uridyltransferase deficiency; Transferase Deficiency Galactosemia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009258; MedGen: C0268151; Orphanet: 352; Orphanet: 79239; OMIM: 230400

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000934199Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 24, 2018)
germlineclinical testing

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

SCV001363672Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 6, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations.

Boutron A, Marabotti A, Facchiano A, Cheillan D, Zater M, Oliveira C, Costa C, Labrune P, Brivet M; French Galactosemia Working Group..

Mol Genet Metab. 2012 Nov;107(3):438-47. doi: 10.1016/j.ymgme.2012.07.025. Epub 2012 Aug 6.

PubMed [citation]
PMID:
22944367

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000934199.1

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

Description

This sequence change replaces asparagine with serine at codon 97 of the GALT protein (p.Asn97Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs111033669, ExAC 0.001%). This variant has been observed in individuals affected with classic galactosemia (PMID: 7550229, 15633893). It is also known as 318A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 25146). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A study of RNA derived from an affected individual has shown that this missense change results in the creation of a cryptic splice site that, when utilized, results in a frameshift (PMID: 7550229). This variant disrupts the p.Asn97 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 22944367), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363672.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: GALT c.290A>G (p.Asn97Ser, legacy name c.318A>G) results in a conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a cryptic 3 acceptor site. A functional study, Ashino_1995 found the variant supports these predictions. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes (gnomAD). c.290A>G has been reported in the literature in individuals affected with Galactosemia (eg. Ashino_1995, Shin_2004, Waisbren_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (eg. Ashino_1995). A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Furthermore, another variant affecting the same codon, N97D, and nearby codons, F95L, D98N, D98H, have been reported in association with Galactosaemia (via HGMD). Therefore, suggesting this region is important for GALT protein function. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Nov 27, 2021

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