NM_000071.3(CBS):c.1039G>A (p.Gly347Ser) AND Classic homocystinuria

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 30, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000169132.7

Allele description [Variation Report for NM_000071.3(CBS):c.1039G>A (p.Gly347Ser)]

NM_000071.3(CBS):c.1039G>A (p.Gly347Ser)

Gene:
CBS:cystathionine beta-synthase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.3
Genomic location:
Preferred name:
NM_000071.3(CBS):c.1039G>A (p.Gly347Ser)
Other names:
p.G347S:GGT>AGT
HGVS:
  • NC_000021.9:g.43062311C>T
  • NG_008938.1:g.18620G>A
  • NM_000071.2:c.1039G>A
  • NM_000071.3:c.1039G>AMANE SELECT
  • NM_001178008.3:c.1039G>A
  • NM_001178009.3:c.1039G>A
  • NM_001320298.2:c.1039G>A
  • NM_001321072.1:c.724G>A
  • NP_000062.1:p.Gly347Ser
  • NP_000062.1:p.Gly347Ser
  • NP_001171479.1:p.Gly347Ser
  • NP_001171480.1:p.Gly347Ser
  • NP_001307227.1:p.Gly347Ser
  • NP_001308001.1:p.Gly242Ser
  • LRG_777t1:c.1039G>A
  • LRG_777:g.18620G>A
  • LRG_777p1:p.Gly347Ser
  • NC_000021.8:g.44482421C>T
Protein change:
G242S
Links:
dbSNP: rs771298943
NCBI 1000 Genomes Browser:
rs771298943
Molecular consequence:
  • NM_000071.2:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000071.3:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178008.3:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178009.3:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320298.2:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321072.1:c.724G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Classic homocystinuria
Synonyms:
HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE; Homocystinuria due to CBS deficiency; Homocystinuria due to cystathionine beta-synthase deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009352; MedGen: C0751202; Orphanet: 394; OMIM: 236200

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220343Counsylcriteria provided, single submitter
Likely pathogenic
(May 22, 2014)
unknownliterature only

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

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000937630Invitaecriteria provided, single submitter
Pathogenic
(Aug 30, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001163818Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

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

SCV001424586Child Health and Human Development Program,Research Institute of the McGill University Health Centerno assertion criteria providedPathogenicunknownclinical testing

SCV001461072Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards.

Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffmann GF.

J Pediatr. 2010 Mar;156(3):427-32. doi: 10.1016/j.jpeds.2009.09.054. Epub 2009 Nov 14.

PubMed [citation]
PMID:
19914636

The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.

Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DE.

Hum Mutat. 2002 Aug;20(2):117-26.

PubMed [citation]
PMID:
12124992
See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000220343.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (7)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000937630.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces glycine with serine at codon 347 of the CBS protein (p.Gly347Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 11 of the CBS coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous or in combination with another CBS variant in several individuals affected with homocystinuria (PMID: 12124992, 16205833, 16307898, 19370759, 24211323). ClinVar contains an entry for this variant (Variation ID: 188801). Experimental studies have shown that this missense change disrupts CBS protein function (PMID: 22267502). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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

From Baylor Genetics, SCV001163818.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Child Health and Human Development Program,Research Institute of the McGill University Health Center, SCV001424586.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testingnot provided

Description

The c.1039G>A (G347S) was identified in a patients of Eastern European origin in compound heterozygote with c.526G>A (E176K). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patients had no intellectual impairment and do not respond to treatment with vitamin B6.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From Natera, Inc., SCV001461072.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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