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NM_000071.3(CBS):c.362G>A (p.Arg121His) AND HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 5, 2023
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:
RCV002228611.4

Allele description [Variation Report for NM_000071.3(CBS):c.362G>A (p.Arg121His)]

NM_000071.3(CBS):c.362G>A (p.Arg121His)

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.362G>A (p.Arg121His)
HGVS:
  • NC_000021.9:g.43066332C>T
  • NG_008938.1:g.14599G>A
  • NM_000071.3:c.362G>AMANE SELECT
  • NM_001178008.3:c.362G>A
  • NM_001178009.3:c.362G>A
  • NM_001320298.2:c.362G>A
  • NM_001321072.1:c.47G>A
  • NP_000062.1:p.Arg121His
  • NP_000062.1:p.Arg121His
  • NP_001171479.1:p.Arg121His
  • NP_001171480.1:p.Arg121His
  • NP_001307227.1:p.Arg121His
  • NP_001308001.1:p.Arg16His
  • LRG_777t1:c.362G>A
  • LRG_777:g.14599G>A
  • LRG_777p1:p.Arg121His
  • NC_000021.8:g.44486442C>T
  • NM_000071.2:c.362G>A
  • P35520:p.Arg121His
Protein change:
R121H
Links:
UniProtKB: P35520#VAR_008055; dbSNP: rs770095972
NCBI 1000 Genomes Browser:
rs770095972
Molecular consequence:
  • NM_000071.3:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178008.3:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178009.3:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320298.2:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321072.1:c.47G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Identifiers:
MedGen: C3150344

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001224398Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 5, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America.

Urreizti R, Asteggiano C, Bermudez M, Córdoba A, Szlago M, Grosso C, de Kremer RD, Vilarinho L, D'Almeida V, Martínez-Pardo M, Peña-Quintana L, Dalmau J, Bernal J, Briceño I, Couce ML, Rodés M, Vilaseca MA, Balcells S, Grinberg D.

J Hum Genet. 2006;51(4):305-313. doi: 10.1007/s10038-006-0362-0. Epub 2006 Feb 15. Erratum in: J Hum Genet. 2007;52(4):388-9. Szlago, Mariana [corrected to Szlago, Marina]. J Hum Genet. 2007 Apr;52(4):388-389. doi: 10.1007/s10038-006-0103-4.

PubMed [citation]
PMID:
16479318

Surrogate genetics and metabolic profiling for characterization of human disease alleles.

Mayfield JA, Davies MW, Dimster-Denk D, Pleskac N, McCarthy S, Boydston EA, Fink L, Lin XX, Narain AS, Meighan M, Rine J.

Genetics. 2012 Apr;190(4):1309-23. doi: 10.1534/genetics.111.137471. Epub 2012 Jan 20. Erratum in: Genetics. 2012 Oct;192(2):759-60.

PubMed [citation]
PMID:
22267502
PMCID:
PMC3316645
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001224398.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 121 of the CBS protein (p.Arg121His). This variant is present in population databases (rs770095972, gnomAD 0.03%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 16479318). ClinVar contains an entry for this variant (Variation ID: 188948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 22267502). This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338090, 16307898, 21520339; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024