chr21-43068519-C-G

Position:

• chr21-43068519-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5 PP3_Strong

The NM_000071.3(CBS):​c.306G>C​(p.Lys102Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K102Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 6)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.43

Genes affected

CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43068521-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.306G>C	p.Lys102Asn	missense_variant	4/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.306G>C	p.Lys102Asn	missense_variant	4/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251330 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Sep 26, 2014

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2023

Variant summary: CBS c.306G>C (p.Lys102Asn) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP 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 4e-06 in 251330 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.306G>C has been reported in the literature as a complex allele in cis alongside c.233C>G (p.Pro78Arg) in a biparentally confirmed compound heterozygous genotype with c.715G>A (p.E239K) (not reported in ClinVar) in trans in two affected siblings with features of Homocystinuria and their unaffected brother (deFranchis_1994). These report(s) do not provide unequivocal conclusions about association of the variant with Homocystinuria. Multiple publications report conflicting variant specific experimental evidence evaluating an impact on protein function in vitro (example, deFranchis_1994, Sen_2007, Mayfield_2012, Hnizda_2012, Melenovska_2015). The most pronounced variant effect results in widely variable CBS activities ranging from 30-50%, 89% or 6% of normal depending upon the expression systems and kinetic parameters evaluated (Ecoli, Yeast, CHO-K1 cells). The complex allele of Pro78Arg+Lys102Asn expressed in cis had 0% activity (deFranchis_1994). Two 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2018

The p.K102N variant (also known as c.306G>C), located in coding exon 2 of the CBS gene, results from a G to C substitution at nucleotide position 306. The lysine at codon 102 is replaced by asparagine, an amino acid with similar properties. This alteration was reported as occurring in cis with p.K102N as a complex allele [P78R:K102N] in three siblings with homocystinuria who had p.E239K in trans. The same study also reported that the complex allele led to abolished CBS activity while the individual variants resulted in reduced activity (de Franchis R et al. Hum. Mol. Genet., 1994 Jul;3:1103-8). The double variant was revealed to lose AdoMet-dependent regulation (Sen S et al. Biochemistry, 2007 Apr;46:4110-6). In addition, follow-up research suggested that the reduced activity of the individual variants might be rescued to some extent by improving protein folding (Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Kopecká J et al. J. Inherit. Metab. Dis., 2011 Feb;34:39-48). However, in yeast assays, this alteration was described to behave similarly to wildtype (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2022

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 102 of the CBS protein (p.Lys102Asn). This variant is present in population databases (rs786204609, gnomAD 0.0009%). This missense change has been observed in individual(s) with CBS deficiency (PMID: 7981678). ClinVar contains an entry for this variant (Variation ID: 188989). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CBS function (PMID: 17352495, 25331909). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;.;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.9	L;L;L;L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.76
MutPred		0.86		Loss of methylation at K102 (P = 0.0079);Loss of methylation at K102 (P = 0.0079);Loss of methylation at K102 (P = 0.0079);Loss of methylation at K102 (P = 0.0079);Loss of methylation at K102 (P = 0.0079);
MVP		0.92
MPC		1.1
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.84
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204609; hg19: chr21-44488629;