ClinVar Miner

Submissions for variant NM_015340.4(LARS2):c.683G>A (p.Arg228His)

dbSNP: rs770440975
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Kids Research, The Children's Hospital at Westmead RCV000993581 SCV000994653 likely pathogenic Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome 2019-07-18 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV002538373 SCV003525148 likely pathogenic not provided 2022-07-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 228 of the LARS2 protein (p.Arg228His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LARS2-related conditions (PMID: 28000701, 30737337, 32442335). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 691519). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LARS2 function (PMID: 32442335). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV002538373 SCV005325904 likely pathogenic not provided 2024-02-20 criteria provided, single submitter clinical testing Published functional studies demonstrate R228H depletes LARS2 amino-acylation activity (PMID: 32442335); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28000701, 34997062, 30737337, 32442335, 35750896)
OMIM RCV001283752 SCV001469100 pathogenic Perrault syndrome 4 2021-01-15 no assertion criteria provided literature only
OMIM RCV000993581 SCV001469101 pathogenic Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome 2021-01-15 no assertion criteria provided literature only

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