ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.215A>T (p.Lys72Ile) (rs192232907)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196407 SCV000249734 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing The K72I variant of uncertain significance in the CBS gene has been reported previously in one Chinese individual with severe homocystinuria who harbored a second variant in the CBS gene (Li et al., 2018). This variant has also been identified both independently of and in conjunction with additional cardiogenetic variants in several individuals referred for TAAD / Marfan syndrome genetic testing at GeneDx. However, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The K72I variant is observed 139/18,848 (0.74%) alleles from individuals of East Asian ancestry in large population cohorts (Lek et al., 2016). The K72I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV001086812 SCV000649830 likely benign Classic homocystinuria 2020-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617440 SCV000738498 benign Cardiovascular phenotype 2017-05-26 criteria provided, single submitter clinical testing General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV001086812 SCV001298525 uncertain significance Classic homocystinuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285369 SCV001471787 uncertain significance none provided 2020-02-23 criteria provided, single submitter clinical testing The CBS c.215A>T; p.Lys72Ile variant (rs192232907) is reported in the literature in an individual affected with coronary artery dissection and another individual affected with homocystinuria (Kaadan 2018, Li 2018). The individual affected with homocystinuria also carried a second missense variant, although the clinical significance of the second variant was not demonstrated (Li 2018). The p.Lys72Ile variant is found in the East Asian population with an overall allele frequency of 0.76% (151/19924 alleles) in the Genome Aggregation Database. The lysine at codon 72 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys72Ile variant is uncertain at this time. References: Kaadan et al. Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection. Circ Genom Precis Med. 2018 Apr;11(4):e001933. Li et al. Eight novel mutations of CBS gene in nine Chinese patients with classical homocystinuria. World J Pediatr. 2018 Apr;14(2):197-203.
Natera, Inc. RCV001086812 SCV001455979 likely benign Classic homocystinuria 2020-05-30 no assertion criteria provided clinical testing

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