Submissions for variant NM_000071.3(CBS):c.1006C>T (p.Arg336Cys)

gnomAD frequency: 0.00002  dbSNP: rs398123151

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169310	SCV000220632	pathogenic	Classic homocystinuria	2014-08-25	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000078105	SCV000225195	pathogenic	not provided	2012-07-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000078105	SCV000249700	pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing	Reported to be a founder mutation in the Qatari population, affecting approximately 1 in 1,8000 births (Gan-Schreier et al., 2010; El Bashir et al., 2015); Functional studies showed reduced activity of R336C in mammalian (Ismail et al., 2019) and E-coli expression systems (Urreizti et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 31240737, 26582918, 30408270, 12815602, 19914636, 27629047, 25218699, 25712383, 7762555, 23685761, 26464485, 10408774, 21517828, 16786517, 21240075, 7967489, 21062078, 16429402, 12124992, 16205833, 19370759, 20455263, 30968424, 31130284)
Fulgent Genetics, Fulgent Genetics	RCV000169310	SCV000893553	pathogenic	Classic homocystinuria	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV002228199	SCV000945559	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 336 of the CBS protein (p.Arg336Cys). This variant is present in population databases (rs398123151, gnomAD 0.004%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 16205833, 21517828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92423). 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. Experimental studies have shown that this missense change affects CBS function (PMID: 10408774, 16205833, 16429402, 26464485). This variant disrupts the p.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9870207, 23974653, 25218699). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280568	SCV001467771	pathogenic	Homocystinuria	2020-12-09	criteria provided, single submitter	clinical testing	Variant summary: CBS c.1006C>T (p.Arg336Cys) results in a non-conservative amino acid change located in the pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250690 control chromosomes (gnomAD). The variant, c.1006C>T, has been reported in the literature in several homozygous and compound heterozygous individuals affected with Homocystinuria (e.g. deFranchis_1999, Urreizti_2003, El-Said_2006, Zaidi_2012); in addition, the variant was identified as a founder mutation in Qatar (El-Said_2006). These data indicate that the variant is very likely to be associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of enzymatic activity (see e.g. deFranchis_1999, Urreizti_2003, Urreizti_2006, Mendes_2015), in addition, recently a transgenic mouse model was also developed with mice showing marked elevation in serum homocysteine (Gupta_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000169310	SCV002016941	pathogenic	Classic homocystinuria	2020-05-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078105	SCV002585903	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169310	SCV004213869	pathogenic	Classic homocystinuria	2023-09-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905038	SCV004736288	pathogenic	CBS-related disorder	2024-01-04	criteria provided, single submitter	clinical testing	The CBS c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Cys. This variant has previously been reported in the homozygous state or with a second causative CBS variant in numerous patients with homocystinuria (Zaidi et al. 2011. PubMed ID: 21517828; Lee et al. 2005. PubMed ID: 16205833; Alcaide et al. 2014. PubMed ID: 25218699; Gaustadnes et al. 2002. PubMed ID: 12124992; de Franchis et al. 1999. PubMed ID: 10408774; Urreizti et al. 2003. PubMed ID: 12815602). This is the most commonly reported causative variant in the CBS gene in individuals in Qatar (El-Said et al. 2006. PubMed ID: 16786517; Zschocke et al. 2009. PubMed ID: 19370759). A different substitution affecting the same amino acid (p.Arg336His) was also reported in patients with homocystinuria (Coude et al.1998. PubMed ID: 9870207; Kumar et al. 2022. PubMed ID: 36065636). In vitro functional studies have shown that both p.Arg336Cys and p.Arg336His substitutions lead to decreased amount of protein and enzyme activity (Lee et al. 2005. PubMed ID: 16205833; Urreizti et al. 2006. PubMed ID: 16429402; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000169310	SCV004804690	pathogenic	Classic homocystinuria	2024-03-17	criteria provided, single submitter	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000169310	SCV001133148	likely pathogenic	Classic homocystinuria	2019-09-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169310	SCV001462108	pathogenic	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing
GeneReviews	RCV000169310	SCV002104266	not provided	Classic homocystinuria		no assertion provided	literature only