ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.1361A>C (p.Tyr454Ser) (rs387906639)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000608744 SCV000731997 uncertain significance not specified 2017-10-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr454Ser variant in HARS has been reported in the homozygous state in 3 Amish individual s with childhood-onset progressive profound hearing loss and retinal abnormaliti es consistent with features of Usher syndrome type III (USH3), but they also pre sented with additional clinical manifestations not usually reported in USH3 pati ents including delayed gross motor development, hyperactive patellar tendon refl exes, mild truncal ataxia, and wide-based gait (Puffenberger 2012). The variant was also detected in 1.7% (7/406) of Amish control chromosomes (Puffenberger 201 2), and in 2/30782 South Asian chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs387906639). In vitro functional studies provide some evidence that the p.Tyr454Ser variant may impact protein f unction (Puffenberger 2012, Abbott 2017); however, these types of assays may not accurately represent biological function. Computational prediction tools and co nservation analysis do not provide strong support for or against an impact to th e protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr454Ser variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting, PM3_Supporting, PS3_Supporting (Richards 2015).
Ambry Genetics RCV000623702 SCV000743014 likely pathogenic Inborn genetic diseases 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000022619 SCV001213691 uncertain significance Usher syndrome, type 3B 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 454 of the HARS protein (p.Tyr454Ser). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs387906639, ExAC 0.006%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22279824). ClinVar contains an entry for this variant (Variation ID: 29756). This variant has been reported to have conflicting or insufficient data to determine the effect on HARS protein function (PMID: 22279524, 28632987). 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.
OMIM RCV000022619 SCV000043908 pathogenic Usher syndrome, type 3B 2012-01-01 no assertion criteria provided literature only

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